Technical Field
[0001] The present invention relates to an axially chiral N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]ac
etamide compound and a chirality inversion method of an α-amino acid using the compound
as a template. The present invention also relates to a metal complex used as an intermediate
for the chirality inversion method, the metal complex having, as a ligand, a condensate
of an α-amino acid and an N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]ac
etamide compound.
Background Art
[0002] Optically pure α-amino acids are useful as a building block for designing various
physiologically active substances and drugs. Recently, it was found that substances
containing, in particular, a D-α-amino acid, which hardly occurs in nature, have unique
physiological effects. Therefore, a process for conveniently obtaining an optically
pure D-α-amino acid as a raw material is desired. Also, peptides and proteins composed
of optically active unnatural synthetic α-amino acids have a more stable higher-order
structure and an improved stability against hydrolytic enzymes than naturally occurring
ones. Therefore, the importance of such optically active unnatural synthetic α-amino
acids in drug development has been increasing, and the development of a process for
conveniently obtaining the optically active α-amino acids is an urgent issue.
[0003] As a production method of an optically active α-amino acid, optical resolution of
a racemic mixture of an α-amino acid is classically known, and recently a fermentation
method or an enzymatic method are known to easily produce L-α-amino acids. Regarding
D-α-amino acids, deracemization of a racemic mixture and chirality inversion from
an easily obtainable L-α-amino acid have been studied. Reported as examples of the
methods are a method using a chiral ligand having an asymmetric carbon atom (see Non
Patent Literature 1 etc.), a method using a chiral ligand having axial chirality (see
Non Patent Literature 2, Patent Literature 1 and 2, etc.), etc.
[0004] However, in each method, there is a problem of generally slow inversion rate. In
particular, in cases of amino acids having a sterically-bulky side chain, such as
valine and isoleucine, there are problems of extremely slow reaction rate and low
optical purity of the obtained product.
[0005] Consequently, none of the known methods are industrially satisfactory, and for the
reason, the development of an industrially applicable production method of an optically
active α-amino acid has been demanded.
Citation List
Patent Literature
Non Patent Literature
Summary of Invention
Technical Problem
[0008] The present inventors made efforts to solve the above problems, and as a result,
successfully created an N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]ac
etamide compound, which can be used as a template in the chirality inversion of an
α-amino acid. By a method the inventors found, an α-amino acid having a desired chirality
is obtained in high yield and in a highly enantioselective manner. The method is as
follows. An S- or R-form of the acetamide compound is selected as appropriate and
condensed with an α-amino acid of which chirality is to be interconverted, and the
condensate is made into a metal complex. The metal complex is subsequently heated
under basic conditions for chirality interconversion of the α-amino acid moiety, and
then subjected to acid treatment to release the chirality-converted α-amino acid as
intended. This method is a generally applicable method for interconverting the chirality
of an α-amino acid as desired in a simple, inexpensive, and industrially advantageous
manner. The present inventors conducted further examination and completed the present
invention.
Solution to Problem
[0009] That is, the present invention includes the following [1] to [9].
- [1] A compound represented by Formula (1):
(wherein R1 denotes hydrogen, an optionally substituted alkyl group (for example, an alkyl group
in which a part or all of the hydrogen atoms are replaced with fluorine atoms), an
optionally substituted alkynyl group, an optionally substituted alkenyl group, an
optionally substituted alkoxy group, an optionally substituted cycloalkyl group, an
optionally substituted aryl group, an optionally substituted heteroaryl group, a halogen
atom, or a nitro group;
R2 denotes hydrogen, an optionally substituted alkyl group (for example, an alkyl group
in which a part or all of the hydrogen atoms are replaced with fluorine atoms), an
optionally substituted alkynyl group, an optionally substituted alkenyl group, an
optionally substituted cycloalkyl group, an optionally substituted aryl group, or
an optionally substituted heteroaryl group;
R3 and R4 each independently denote hydrogen, an optionally substituted alkyl group (for example,
an alkyl group in which a part or all of the hydrogen atoms are replaced with fluorine
atoms), an optionally substituted alkynyl group, an optionally substituted alkenyl
group, an optionally substituted alkoxy group, an optionally substituted cycloalkyl
group, an optionally substituted aryl group, an optionally substituted heteroaryl
group, or a halogen atom;
the two R3s may be the same or different;
the two R4s may be the same or different;
R3 and R4 may form a ring together with the carbon atoms to which they are bonded;
R5 denotes hydrogen, an optionally substituted alkyl group (for example, an alkyl group
in which a part or all of the hydrogen atoms are replaced with fluorine atoms), an
optionally substituted alkynyl group, an optionally substituted alkenyl group, an
optionally substituted alkoxy group, an optionally substituted cycloalkyl group, an
optionally substituted aryl group, an optionally substituted heteroaryl group, a carboxyl
group, a halogen atom, -COOR7, or -C(OH)(R7)2;
the two R5s may be the same or different;
R6 denotes hydrogen, an optionally substituted alkyl group, an optionally substituted
cycloalkyl group, or a halogen atom;
the two R6s may be the same or different;
the two R6s may form a ring together with the carbon atom to which they are bonded;
R7 denotes hydrogen, an optionally substituted alkyl group, an optionally substituted
aryl group, or an optionally substituted heteroaryl group; and
* denotes a chiral axis),
or a salt thereof.
- [2] The compound according to the above [1] or a salt thereof, wherein, in each of
the two pairs of R3 and R4 in Formula (1), R3 and R4 form an aromatic ring or an alicyclic structure together with the aromatic-ring carbon
atoms to which they are bonded; and
R2 denotes a group represented by the following formula:
(wherein R8 denotes a hydrogen atom or a halogen atom), the compound being represented by Formula
(2):
(wherein R1, R5 and R6 have the same meanings as defined in the above [1]).
- [3] The compound according to the above [2] or a salt thereof, wherein R1 is hydrogen, chlorine, a methyl group, or a nitro group; and R5 and R6 are each hydrogen.
- [4] A metal complex represented by Formula (3):
(wherein R1 denotes hydrogen, an optionally substituted alkyl group (for example, an alkyl group
in which a part or all of the hydrogen atoms are replaced with fluorine atoms), an
optionally substituted alkynyl group, an optionally substituted alkenyl group, an
optionally substituted alkoxy group, an optionally substituted cycloalkyl group, an
optionally substituted aryl group, an optionally substituted heteroaryl group, a halogen
atom, or a nitro group;
R2 denotes hydrogen, an optionally substituted alkyl group, an optionally substituted
alkynyl group, an optionally substituted alkenyl group, an optionally substituted
cycloalkyl group, an optionally substituted aryl group, or an optionally substituted
heteroaryl group,
R3 and R4 each independently denote hydrogen, an optionally substituted alkyl group (for example,
an alkyl group in which a part or all of the hydrogen atoms are replaced with fluorine
atoms), an optionally substituted alkynyl group, an optionally substituted alkenyl
group, an optionally substituted alkoxy group, an optionally substituted cycloalkyl
group, an optionally substituted aryl group, an optionally substituted heteroaryl
group, or a halogen atom;
the two R3s may be the same or different;
the two R4s may be the same or different;
R3 and R4 may form a ring together with the carbon atoms to which they are bonded;
R5 denotes hydrogen, an optionally substituted alkyl group (for example, an alkyl group
in which a part or all of the hydrogen atoms are replaced with fluorine atoms), an
optionally substituted alkynyl group, an optionally substituted alkenyl group, an
optionally substituted alkoxy group, an optionally substituted cycloalkyl group, an
optionally substituted aryl group, an optionally substituted heteroaryl group, a carboxyl
group, a halogen atom, -COOR7, or -C(OH)(R7)2;
the two R5s may be the same or different;
R6 denotes hydrogen, an optionally substituted alkyl group, an optionally substituted
cycloalkyl group, or a halogen atom;
the two R6s may be the same or different;
the two R6s may form a ring together with the carbon atom to which they are bonded;
R7 denotes hydrogen, an optionally substituted alkyl group, an optionally substituted
aryl group, or an optionally substituted heteroaryl group;
R9 denotes an optionally substituted alkyl group (for example, an alkyl group in which
a part or all of the hydrogen atoms are replaced with fluorine atoms), an optionally
substituted alkynyl group, an optionally substituted alkenyl group, an optionally
substituted cycloalkyl group, an optionally substituted aryl group, an optionally
substituted heteroaryl group, an optionally substituted aralkyl group, or an optionally
substituted heteroarylalkyl group;
* denotes a chiral axis; and
M denotes a divalent metallic cation).
- [5] The metal complex according to the above [4], wherein, in each of the two pairs
of R3 and R4 in Formula (3), R3 and R4 form an aromatic ring or an alicyclic structure together with the aromatic-ring carbon
atoms to which they are bonded; and
R2 denotes a group represented by the following formula:
(wherein R8 denotes a hydrogen atom or a halogen atom), the metal complex being represented by
Formula (4):
(wherein R1, R5 and R6 have the same meanings as defined in the above [4]).
- [6] The metal complex according to the above [4] or [5], wherein R1 is hydrogen, chlorine, a methyl group, or a nitro group; in each of the two pairs
of R3 and R4, R3 and R4 form an aromatic ring or an alicyclic structure together with the aromatic-ring carbon
atoms to which they are bonded; R5 and R6 are each hydrogen; and M denotes a nickel cation, a copper cation, a palladium cation,
or a platinum cation.
- [7] A method for interconverting the configuration of an α-amino acid, the method
comprising heating, under basic conditions, the divalent metal cation complex represented
by Formula (3) in claim 4 derived from an imine compound produced from a selected
optically active R- or S-form of the N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]ac
etamide compound represented by Formula (1) in claim 1 or a salt thereof and an α-amino
acid in order to convert the configuration of the α carbon in the α-amino acid moiety,
and subjecting the metal complex to acid decomposition to give an optically pure α-amino
acid enantiomer having a converted configuration.
- [8] The method according to the above [7], wherein the α-amino acid or a salt thereof
is represented by Formula (5):
(wherein R9 is as defined in the above [4]) and is a mixture of optical isomers, or a pure optical
isomer.
[0010] As an alternative, a method for converting the chirality (configuration) of an α-amino
acid, the method comprising heating, under basic conditions, the divalent metal cation
complex represented by Formula (3) in the above [4] derived from an imine compound
produced from an optically active N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]ac
etamide compound having a selected R- or S-configuration represented by Formula (1)
in the above [1] or a salt thereof and an α-amino acid represented by Formula (5)
in order to convert the configuration of the α carbon in the α-amino acid moiety via
an enolate intermediate, and decomposing the metal complex using an acid to give an
α-amino acid enantiomer having a desired configuration.
[0011] As an alternative, a method for converting the chirality (configuration) of an α-amino
acid, the method comprising heating, under basic conditions, the divalent metal cation
complex represented by Formula (3) in the above [4] derived from an imine compound
produced from an optically active N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]
acetamide compound having a selected R- or S-configuration represented by Formula
(1) in the above [1] or a salt thereof and an α-amino acid represented by Formula
(5) for inverting the configuration of the α carbon in the α-amino acid moiety to
L-form in cases where the compound represented by Formula (1) is of R-form and to
D-form in cases where the compound represented by Formula (1) is of S-form, and subsequently
acid decomposing the metal complex to release the chirality-inverted α-amino acid
and thereby give an optically pure α-amino acid enantiomer.
[0012] In Formula (5), R
9 denotes an optionally substituted alkyl group (for example, an alkyl group in which
a part or all of the hydrogen atoms are replaced with fluorine atoms; the same applies
to other substituents, such as an alkynyl group, an alkenyl group, a cycloalkyl group,
and an aryl group), an optionally substituted alkynyl group, an optionally substituted
alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted
aryl group, an optionally substituted heteroaryl group, an optionally substituted
aralkyl group, or an optionally substituted heteroarylalkyl group.
[8] The method according to the above [7], wherein the α-amino acid represented by
Formula (5) before chirality conversion is a mixture of optical isomers or a pure
optical isomer.
[9] The method according to the above [7] or [8], wherein the N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]
acetamide compound is the compound represented by Formula (1) in the above [1].
[0013] The reaction chart of the present invention is as follows.
Advantageous Effects of Invention
[0014] An object of the present invention is to produce an optically active α-amino acid
having a desired chirality in high yield and in a highly enantioselective manner by
chirality conversion of an α-amino acid, and the present invention provides, among
others, a novel N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]ac etamide
compound as an indispensable chiral template used for the production. The present
invention relates to a metal complex of a condensate of an α-amino acid and an optically
active N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]ac etamide compound
having axial chirality. Through the intermediacy of the above metal complex, the chirality
interconversion of an α-amino acid is easily performed, and thereby an α-amino acid
having a desired chirality can be produced in a convenient and inexpensive manner.
Brief Description of Drawings
[0015]
Fig. 1 shows a HPLC analysis result of a Ni(II) complex obtained in Example 2-1, which
has D-phenylalanine as a partial structure.
Fig. 2 shows a HPLC analysis result of a Ni(II) complex obtained in Example 2-2, which
has L-phenylalanine as a partial structure.
Fig. 3 shows a HPLC analysis result of a Ni(II) complex obtained in Example 2-3, which
has D-leucine as a partial structure.
Fig. 4 shows a HPLC analysis result of a Ni(II) complex obtained in Example 2-4, which
has D-methionine as a partial structure.
Fig. 5 shows a HPLC analysis result of a Ni(II) complex obtained in Example 2-5, which
has D-tryptophan as a partial structure.
Fig. 6 shows a HPLC analysis result of a Ni(II) complex obtained in Example 2-6, which
has D-glutamine as a partial structure.
Fig. 7 shows a 1H-NMR spectrum of a Ni (II) complex obtained in Example 2-7, which has D-glutamic
acid as a partial structure.
Fig. 8 shows a HPLC analysis result of the L-phenylalanine protected by a Z group
(Z-L-phenylalanine) obtained in Example 3-1.
Fig. 9 shows a HPLC analysis result of the D-phenylalanine protected by a Z group
obtained in Example 3-2.
Fig. 10 shows a HPLC analysis result of the dicyclohexylamine salt of D-lysine protected
by Z groups (Z-D-Lys(Z)) obtained in Example 3-3.
Fig. 11 shows a HPLC analysis result of a Ni(II) complex obtained in Example 4-1-1,
which has D-phenylalanine as a partial structure.
Fig. 12 shows a HPLC analysis result of a Ni(II) complex obtained in Example 4-1-2,
which has D-phenylalanine as a partial structure.
Fig. 13 shows a HPLC analysis result of a Ni(II) complex obtained in Example 4-2-1,
which has L-phenylalanine as a partial structure.
Fig. 14 shows a HPLC analysis result of a Ni(II) complex obtained in Example 4-2-2,
which has L-phenylalanine as a partial structure.
Fig. 15 shows a HPLC analysis result of a Ni(II) complex obtained in Example 4-3,
which has D-valine as a partial structure.
Fig. 16 shows a HPLC analysis result of a Ni(II) complex obtained in Example 4-4,
which has L-valine as a partial structure.
Fig. 17 shows a HPLC analysis result of a Ni(II) complex obtained in Example 4-5,
which has D-alanine as a partial structure.
Fig. 18 shows a HPLC analysis result of a Ni(II) complex obtained in Example 4-6,
which has L-alanine as a partial structure.
Fig. 19 shows a HPLC analysis result of a Ni(II) complex obtained in Example 4-7,
which has D-tyrosine as a partial structure.
Description of Embodiments
[0016] The chemical reactions involved in the present invention are as follows. (Indication
of salts is omitted.)
- (i) An imine compound produced by condensation of an optically active N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]ac
etamide compound represented by Formula (1) and an α-amino acid represented by Formula
(5) is reacted with a metal salt MXn to give a metal complex represented by Formula
(3);
- (ii) the metal complex represented by Formula (3) is heated under basic conditions
to be led into a metal complex having stereochemically converted configuration of
the α-amino acid moiety, which metal complex is represented by Formula (3'); and
- (iii) the metal complex represented by Formula (3') having stereochemically converted
configuration is subjected to acid decomposition to give the α-amino acid having a
desired configuration through chirality conversion represented by Formula (5').
[0017] The above steps of (i) and (ii) can be performed continuously.
[0018] The compound represented by Formula (1) has two optical isomers represented by Formula
(1A, S-isomer) and Formula (1B, R-isomer). In the method of the present invention,
the optical isomer represented by Formula (1A, S-isomer) converts an L-form α-amino
acid into a D-form counterpart but does not change the configuration of the α carbon
atom in a D-form α-amino acid. Meanwhile, in the method of the present invention,
the optical isomer represented by Formula (1B, R-isomer) converts a D-form α-amino
acid into an L-form counterpart but does not change the configuration of the α carbon
atom in an L-form α-amino acid.
[0019] That is, the present invention includes a method for converting an L-form α-amino
acid into a D-form counterpart, a method for converting a D-form α-amino acid into
an L-form counterpart, and a method for completely converting a racemic α-amino acid
into an optically pure α-amino acid having single chirality at the α carbon, by using
an appropriately selected optical isomer represented by Formula (1A, S-isomer) or
Formula (1B, R-isomer).
[0020] In the present invention, "pure" means an industrially acceptable level of optical
purity. The optical purity is not particularly limited, but usually about 90% or more,
preferably about 95% or more.
[0021] The α-amino acid used in the present invention may be L-form, D-form, or a mixture
thereof at any ratio, and is preferably an α-amino acid represented by Formula (5):
or a salt thereof. R
9 may be an optionally substituted alkyl group (for example, an alkyl group in which
a part or all of the hydrogen atoms are replaced with fluorine atoms; the same applies
to other substituents, such as an alkynyl group, an alkenyl group, a cycloalkyl group,
and an aryl group), an optionally substituted alkynyl group, an optionally substituted
alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted
aryl group, an optionally substituted heteroaryl group, an optionally substituted
aralkyl group, or an optionally substituted heteroarylalkyl group.
[0022] According to the method of the present invention, a desired optically active amino
acid can be produced in high yield and in a highly enantioselective manner.
[0023] The optically active N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]ac
etamide compound used in the present invention is represented by the following Formula
(1):
(wherein R1 denotes hydrogen, an optionally substituted alkyl group (for example, an alkyl group
in which a part or all of the hydrogen atoms are replaced with fluorine atoms), an
optionally substituted alkynyl group, an optionally substituted alkenyl group, an
optionally substituted alkoxy group, an optionally substituted cycloalkyl group, an
optionally substituted aryl group, an optionally substituted heteroaryl group, a halogen
atom, or a nitro group;
R2 denotes hydrogen, an optionally substituted alkyl group, an optionally substituted
alkynyl group, an optionally substituted alkenyl group, an optionally substituted
cycloalkyl group, an optionally substituted aryl group, or an optionally substituted
heteroaryl group,
R3 and R4 each independently denote hydrogen, an optionally substituted alkyl group (for example,
an alkyl group in which a part or all of the hydrogen atoms are replaced with fluorine
atoms), an optionally substituted alkynyl group, an optionally substituted alkenyl
group, an optionally substituted alkoxy group, an optionally substituted cycloalkyl
group, an optionally substituted aryl group, an optionally substituted heteroaryl
group, or a halogen atom;
the two R3s may be the same or different;
the two R4s may be the same or different;
R3 and R4 may form a ring together with the carbon atoms to which they are bonded;
R5 denotes hydrogen, an optionally substituted alkyl group (for example, an alkyl group
in which a part or all of the hydrogen atoms are replaced with fluorine atoms), an
optionally substituted alkynyl group, an optionally substituted alkenyl group, an
optionally substituted alkoxy group, an optionally substituted cycloalkyl group, an
optionally substituted aryl group, an optionally substituted heteroaryl group, a carboxyl
group, a halogen atom, -COOR7, or -C(OH)(R7)2;
the two R5s may be the same or different;
R6 denotes hydrogen, an optionally substituted alkyl group, an optionally substituted
cycloalkyl group, or a halogen atom;
the two R6s may be the same or different;
the two R6s may form a ring together with the carbon atom to which they are bonded;
R7 denotes hydrogen, an optionally substituted alkyl group, an optionally substituted
aryl group, or an optionally substituted heteroaryl group; and
* denotes a chiral axis).
[0024] The "alkyl group" in the optionally substituted alkyl group denoted by R
1 is not particularly limited and may be linear or branched. Examples of the "alkyl
group" include alkyl groups having 1 to 20 carbon atoms, specifically, a methyl group,
an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group,
a sec-butyl group, a tert-butyl group, a pentyl group, an hexyl group, a heptyl group,
an octyl group, a nonyl group, a decyl group, a dodecyl group, a pentadecyl group,
a hexadecyl group, an octadecyl group, and the like.
[0025] The "alkynyl group" in the optionally substituted alkynyl group denoted by R
1 is not particularly limited. Examples of the "alkynyl group" include alkynyl groups
having 2 to 20 carbon atoms, specifically, an ethynyl group, a propynyl group, and
the like.
[0026] The "alkenyl group" in the optionally substituted alkenyl group denoted by R
1 is not particularly limited. Examples of the "alkenyl group" include alkenyl groups
having 2 to 20 carbon atoms, specifically, a vinyl group, an allyl group, a butenyl
group, a hexenyl group, and the like.
[0027] The "alkoxy group" in the optionally substituted alkoxy group denoted by R
1 is not particularly limited. Examples of the "alkoxy group" include alkoxy groups
having 1 to 20 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy
group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group,
a tert-butoxy group, a pentyloxy group, and the like.
[0028] The "cycloalkyl group" in the optionally substituted cycloalkyl group denoted by
R
1 is not particularly limited. Examples of the "cycloalkyl group" include cycloalkyl
groups having 3 to 12 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl
group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.
[0029] The "aryl group" in the optionally substituted aryl group denoted by R
1 is not particularly limited. Examples of the "aryl group" include aryl groups having
6 to 20 carbon atoms, specifically, a phenyl group, a 1-naphthyl group, a 2-naphthyl
group, an anthryl group, a phenanthryl group, a 2-biphenyl group, a 3-biphenyl group,
a 4-biphenyl group, a terphenyl group, and the like.
[0030] The "heteroaryl group" in the optionally substituted heteroaryl group denoted by
R
1 is not particularly limited. Examples of the " heteroaryl group" include heteroaryl
groups having 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom, an
oxygen atom, etc., specifically, a furanyl group, a thienyl group, an oxazolyl group,
an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a pyrrolyl group, an
imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl
group, a phthalazinyl group, a triazinyl group, an indolyl group, an isoindolyl group,
a quinolinyl group, an isoquinolinyl group, a dibenzofuranyl group, and the like.
[0031] The halogen atom denoted by R
1 is not particularly limited. Examples of the halogen atom include a fluorine atom,
a chlorine atom, a bromine atom, an iodine atom, and the like.
[0032] The "substituent" in R
1 is not particularly limited. Examples of the above "substituent" include an alkyl
group (for example, a methyl group, an ethyl group, a propyl group, an isopropyl group,
a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl
group, an hexyl group, and the like); an alkynyl group (for example, an ethynyl group,
a propynyl group and the like); an alkenyl group (for example, a vinyl group, an allyl
group, a butenyl group, a hexenyl group, and the like); an alkoxy group (for example,
a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group,
an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and
the like) ; a cycloalkyl group (for example, a cyclopropyl group, a cyclobutyl group,
a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like) ; an aryl
group (for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an anthryl
group, a phenanthryl group, a 2-biphenyl group, a 3-biphenyl group, a 4-biphenyl group,
a terphenyl group, and the like) ; a heteroaryl group (for example, a furanyl group,
a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl
group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group,
a pyrimidinyl group, a pyrazinyl group, a phthalazinyl group, a triazinyl group, an
indolyl group, an isoindolyl group, a quinolinyl group, an isoquinolinyl group, a
dibenzofuranyl group, and the like); an aralkyl group (for example, a phenylethyl
group, a phenylpropyl group, a naphthyl methyl group, and the like); a haloalkyl group
(for example, a trifluoromethyl group, a trichloromethyl group, and the like) ; a
halogenated alkoxy group (for example, a fluoromethoxy group, a difluoromethoxy group,
a trifluoromethoxy group, a trifluoroethoxy group, a tetrafluoroethoxy group, and
the like); a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine
atom, an iodine atom, and the like) ; a hydroxyl group; a protected hydroxyl group
(examples of the protecting group for the hydroxyl group include an acetyl group,
a benzoyl group, a methoxymethyl group, a tetrahydropyranyl group, a trimethylsilyl
group, a tert-butyldimethylsilyl group, a carbonate ester group, and the like); an
amino group; a protected amino group (examples of the protecting group for the amino
group, include a formyl group, an acetyl group, a benzoyl group, a benzyloxycarbonyl
group, a phthaloyl group, a carbamoyl group, a ureido group, a tert-butoxycarbonyl
group, a 9-fluorenylmethyloxycarbonyl group, and the like); an arylamino group; a
heteroarylamino group; a mercapto group; a nitro group; a nitrile group; a carboxyl
group; an alkoxycarbonyl group; and the like. The number of carbon atoms in these
substituents is not particularly limited, but preferably 1 to 10.
[0033] The number of "substituents" in R
1 is not particularly limited. The number of "substituents" in R
1 has only to be, for example, 1 to 4, is preferably 1 to 2, and more preferably 1.
[0034] The position at which R
1 is bonded is not particularly limited. The position at which R
1 is bonded may be any of positions 3, 4, 5, and 6, but is preferably position 4.
[0035] Examples of the optionally substituted alkyl group, the optionally substituted alkynyl
group, the optionally substituted alkenyl group, the optionally substituted cycloalkyl
group, the optionally substituted aryl group, or the optionally substituted heteroaryl
group, denoted by R
2 include those listed for R
1, for example. Examples of the substituent in this case include those mentioned above
for R
1, for example.
[0036] Examples of the optionally substituted alkyl group, the optionally substituted alkynyl
group, the optionally substituted alkenyl group, the optionally substituted alkoxy
group, the optionally substituted cycloalkyl group, the optionally substituted aryl
group, or the optionally substituted heteroaryl group, or the halogen atom, denoted
by R
3 or R
4 include those listed for R
1, for example. Examples of the substituent in this case include those mentioned above
for R
1, for example.
[0037] The ring formed of R
3 and R
4 together with the carbon atoms to which they are bonded is not particularly limited,
and may be an alicyclic ring or an aromatic ring. Examples of the above ring include
a cycloalkane ring, a cycloalkene ring, an aryl ring, a heteroaryl ring, and the like,
specifically, cyclopentane, cyclohexane, cyclopentene, cyclohexene, a benzene ring,
a naphthalene ring, a pyridine ring, and the like. The number of carbon atoms in the
above ring is not particularly limited, but preferably 3 to 15.
[0038] Examples of the optionally substituted alkyl group, the optionally substituted alkynyl
group, the optionally substituted alkenyl group, the optionally substituted alkoxy
group, the optionally substituted cycloalkyl group, the optionally substituted aryl
group, or the optionally substituted heteroaryl group, or the halogen atom, denoted
by R
5 include those listed for R
1, for example. Examples of the substituent in this case include those mentioned above
for R
1, for example.
[0039] Examples of the optionally substituted alkyl group, the optionally substituted cycloalkyl
group, or a halogen atom, denoted by R
6 include those listed for R
1, for example. Examples of the substituent in this case include those mentioned above
for R
1, for example.
[0040] Examples of the optionally substituted alkyl group, the optionally substituted aryl
group, or the optionally substituted heteroaryl group, denoted by R
7 include those listed for R
1, for example. Examples of the substituent in this case include those mentioned above
for R
1, for example.
[0041] R
1 is preferably hydrogen, chlorine, a methyl group, or a nitro group.
[0042] R
2 is preferably an optionally substituted aryl group, and more preferably a phenyl
group, or a phenyl group substituted with a halogen atom.
[0043] The two R
3s are preferably the same. Also, the two R
4s are preferably the same. Also, R
3 and R
4 more preferably form a ring together with the carbon atoms to which they are bonded.
[0044] The two R
5s are preferably the same, and more preferably each hydrogen.
[0045] The two R
6s are preferably the same, and more preferably each hydrogen.
[0046] The "chiral axis" herein denoted by * means such a bond axis that restriction of
the rotation about the axis produces chirality. The "chiral axis" includes, for example,
an axis about which a set of ligands is held in a spatial arrangement that is not
superposable on its mirror image and an axis as the line of intersection of two mutually
perpendicular planes of a molecule not having a plane of symmetry.
[0047] The compound represented by Formula (1) is preferably a compound represented by Formula
(2):
(wherein R
1, R
5, R
6, and * have the same meanings as defined above, and R
8 denotes a hydrogen or halogen atom),
wherein R
3 and R
4 form an aromatic ring or an alicyclic structure together with the carbon atoms to
which they are bonded.
[0048] Examples of the halogen atom denoted by R
8 include halogen atoms listed for R
1, for example. R
8 is preferably hydrogen, fluorine, or chlorine.
[0049] Examples of the compound represented by Formula (2) or a salt thereof include the
following compounds represented by Structural Formulae (2-1) to (2-7) or salts thereof,
for example.
[0050] Examples of the salt of the optically active N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]ac
etamide compound in the present invention include a salt with an inorganic acid, such
as hydrochloric acid, sulfuric acid, and phosphoric acid; a salt with an organic acid,
such as acetic acid and benzenesulfonic acid; etc.
[0051] The compound represented by Formula (1) or a salt thereof, of which the production
method is not particularly limited, can be produced by the reaction shown below, for
example. That is, by the reaction of the compound represented by Formula (7):
(wherein R1 and R2 have the same meanings as defined above) or a salt thereof,
the compound represented by Formula (8):
(wherein R6 has the same meaning as defined above, and L1 and L2 independently denote a leaving group) or a salt thereof, and the compound represented
by Formula (9):
(wherein R3, R4, R5, and * have the same meanings as defined above) or a salt thereof,
the compound represented by Formula (1) or a salt thereof can be produced.
[0052] The compound represented by Formula (7) or a salt thereof may be produced by a known
method or be a commercial product. As the compound represented by Formula (7) or a
salt thereof, substances described in a document (
T. K. Ellis et al., J. Org. Chem., 2006, 71, 8572-8578), for example, can be used.
[0053] The compound represented by Formula (7) is preferably a compound represented by Formula
(7-1):
(wherein R
1 and R
8 have the same meanings as defined above).
[0054] In the compound represented by Formula (7-1) or a salt thereof, examples of R
1 include those listed for Formula (1), for example. In the compound represented by
Formula (7-1) or a salt thereof, examples of R
8 include those listed for Formula (2), for example.
[0055] In the compound represented by Formula (8):
(wherein R6, L1, and L2 have the same meanings as defined above) or a salt thereof,
L1 and L2 independently denote a leaving group. The leaving group is not particularly limited
as long as it is a generally known leaving group, and examples thereof include a halogen
atom, a tosylate (OTs), and a mesylate (OMs).
L1 and L2 are preferably a halogen atom, and more preferably a chlorine atom or a bromine atom.
L1 and L2 are preferably the same group as each other, and more preferably each a halogen atom.
[0056] Examples of the compound represented by Formula (8) include ClCH
2COCl, BrCH
2COBr, etc.
[0057] The compound represented by Formula (8) or a salt thereof can be produced by a known
method. As an acetanilide compound derived from the compound represented by Formula
(8), substances described in a document (
T. K. Ellis et al., J. Org. Chem., 2006, 71, 8572-8578), for example, can be used.
[0059] The compound represented by Formula (9) is preferably a compound represented by Formula
(10):
(wherein R
5 and * have the same meanings as defined above).
[0060] In the compound represented by Formula (10), examples of R
5 and R
7 include those listed for Formula (1), for example.
[0061] In the above-mentioned production method of the compound represented by Formula (1)
or a salt thereof, the conditions for the reaction of the compound represented by
Formula (7) or a salt thereof, the compound represented by Formula (8) or a salt thereof,
and the compound represented by Formula (9) or a salt thereof is not particularly
limited, but preferred are the conditions shown below.
[0062] The amount of the compound represented by Formula (8) or a salt thereof used is not
particularly limited as long as the reaction proceeds. Specifically, the amount of
the compound represented by Formula (8) or a salt thereof used may usually be about
0.5 to 10 mol, more preferably about 1.0 to 3.0 mol, relative to 1 mol of the compound
represented by Formula (7) or a salt thereof, for example.
[0063] The amount of the compound represented by Formula (9) or a salt thereof used is not
particularly limited as long as the reaction proceeds. Specifically, the amount of
the compound represented by Formula (9) or a salt thereof used may usually be about
0.5 to 5.0 mol, more preferably about 0.5 to 2.0 mol, relative to 1 mol of the compound
represented by Formula (7) or a salt thereof, for example.
(Solvent)
[0064] In the above-mentioned production method of the compound represented by Formula (1)
or its salt, the solvent used for the reaction is not particularly limited, and examples
thereof include organic solvents, such as alcohols (methanol, ethanol, isopropyl alcohol,
tert-butanol, etc.); ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,
etc.); halohydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride,
etc.); aromatic hydrocarbons (benzene, toluene, xylene, pyridine, etc.); aliphatic
hydrocarbons (hexane, pentane, cyclohexane, etc.); nitriles (acetonitrile, propionitrile,
etc.); and amides (N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone).
Among these, from the viewpoint of reaction efficiency, preferred are acetonitrile,
propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,
etc.
(Base)
[0065] In the above-mentioned production method of the compound represented by Formula (1)
or its salt, the base used for the reaction is not particularly limited, and examples
thereof include potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium hydrogen
carbonate, potassium carbonate, sodium carbonate, cesium carbonate, sodium acetate,
potassium acetate, lithium acetate, sodium benzoate, lithium benzoate, etc. Among
these, from the viewpoint of reaction efficiency, preferred are potassium hydroxide,
sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium
carbonate, etc.
(Separation and purification)
[0066] In the above-mentioned production method of the compound represented by Formula (1)
or its salt, an optically pure objective substance can be obtained by a known separation
and/or purification method, which is not particularly limited. Examples of the known
separation and/or purification method include, for example, concentration; extraction;
filtration; washing; crystallization; recrystallization; formation of a salt with
an achiral acid, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, formic
acid, trifluoroacetic acid, etc. and recrystallization thereof; and chemical optical
resolution using a chiral acid such as mandelic acid, tartaric acid, dibenzoyltartaric
acid, ditoluoyltartaric acid, camphor-10-sulfonic acid, and malic acid, a column for
optical isomer separation, etc.; and the like.
[0067] More specifically, in the above-mentioned production method of the compound represented
by Formula (1) or its salt, an additional step of separation and/or purification may
be performed to obtain an optically pure objective substance. The separation and/or
purification method is not particularly limited, and various methods usually used
in this field may be used. Specific examples of the separation method include concentration,
extraction, filtration, washing, etc., and specific examples of the purification method
include crystallization (recrystallization, suspension, etc.), selective dissolution,
physical optical resolution using a column for optical isomer separation, etc., and
the like. Examples of the recrystallization include formation of a salt with an achiral
acid (hydrochloric acid, sulfuric acid, methanesulfonic acid, formic acid, trifluoroacetic
acid, etc.), the diastereomeric salt formation method using a chiral acid (mandelic
acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, camphor-10-sulfonic
acid, malic acid), and the like.
[0068] The metal complex represented by Formula (3) is also a constituent of the present
invention.
[0069] In the metal complex represented by Formula (3):
(wherein R1, R2, R3, R4, R5, R6, and * have the same meanings as defined above;
R9 denotes an optionally substituted alkyl group, an optionally substituted alkynyl
group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl
group, an optionally substituted aryl group, an optionally substituted heteroaryl
group, an optionally substituted aralkyl group, or an optionally substituted heteroarylalkyl
group; and
M denotes a divalent metallic cation),
examples of R
1 to R
6 include those listed for Formula (1), for example.
[0070] In the metal complex represented by Formula (3), M denotes a divalent metallic cation.
The divalent metallic cation is not particularly limited, and examples thereof include
cations of alkaline earth metals, such as magnesium, calcium, strontium, and barium;
cations of transition metals, such as cadmium, titanium, zirconium, nickel (II), palladium,
platinum, zinc, copper (II), mercury (II), iron (II), cobalt (II), tin (II), lead
(II), and manganese (II); etc. Among them, preferred is a cation of nickel, copper,
palladium, or platinum.
[0071] In the metal complex represented by Formula (3), examples of the optionally substituted
alkyl group, the optionally substituted alkynyl group, the optionally substituted
alkenyl group, the optionally substituted cycloalkyl group, the optionally substituted
aryl group, or the optionally substituted heteroaryl group, denoted by R
9 include those listed for R
1, for example.
[0072] Examples of the optionally substituted aralkyl group denoted by R
9 include the above-mentioned alkyl groups of which a hydrogen atom is replaced by
an aryl group, and specific examples thereof include a benzyl group, a phenylethyl
group, a phenylpropyl group, a naphthylmethyl group, etc.
[0073] Examples of the "heteroaryl group" in the optionally substituted heteroarylalkyl
group denoted by R
9 include heteroaryl groups having 1 to 3 heteroatoms selected from a nitrogen atom,
a sulfur atom, an oxygen atom, etc., and specific examples thereof include a furanyl
group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group,
an isothiazolyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a
pyridyl group, a pyrimidinyl group, a pyrazinyl group, a phthalazinyl group, a triazinyl
group, an indolyl group, an isoindolyl group, a quinolinyl group, an isoquinolinyl
group, a dibenzofuranyl group, and the like.
[0074] In the metal complex represented by Formula (3), the α-amino acid moiety including
R
9 has a chiral center. Also, in the metal complex represented by Formula (3), the biphenyl
moiety has axial chirality as shown by *.
[0075] The metal complex represented by Formula (3) is preferably a metal complex represented
by Formula (4):
(wherein R
1, R
5, R
6, R
8, R
9, M, and * have the same meanings as defined above), wherein R
3 and R
4 form an aromatic ring or an alicyclic structure together with the carbon atoms to
which they are bonded.
[0076] In the metal complex represented by Formula (4), examples of R
1, R
5, and R
6 include those listed for Formula (1), for example. Also, in the metal complex represented
by Formula (4), examples of R
9 and M include those listed for Formula (3), for example. Examples of R
8 include those listed for Formula (2), for example.
[0077] A preferable production method of the metal complex represented by Formula (3) or
Formula (4) will be shown below. That is, by the reaction of an optically active α-amino
acid represented by Formula (5):
(wherein R
9 has the same meaning as defined above) or a mixture thereof as a raw material, a
compound represented by Formula (1) :
(wherein each sign has the same meaning as defined for the above Formula (1)) or a
salt thereof, and a metal compound represented by Formula (6):
MX
n (6)
(wherein M denotes a divalent metallic cation; and X denotes a univalent or divalent
anion, when X is a univalent anion, n is 2, and when X is a divalent anion, n is 1)
in the presence of a base, a metal complex represented by Formula (3):
(wherein each sign has the same meaning as defined for the above Formula (3)) can
be obtained.
[0078] Examples of the α-amino acid represented by Formula (5) or a salt thereof include
α-amino acids, such as alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid
(Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), histidine (His), isoleucine
(Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), serine
(Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), valine (Val), etc. and unnatural
synthetic α-amino acids, and salts thereof. These α-amino acids or salts thereof may
be L-form, D-form, or mixtures thereof at any ratio.
[0079] In the above production method, after the α-amino acid represented by Formula (5)
or a salt thereof as a raw material, the compound represented by Formula (1) or a
salt thereof, and the metal compound represented by Formula (6) or a salt thereof,
were mixed, the mixture is preferably heated. As a result, the metal complex represented
by Formula (3) as the objective substance can be obtained in higher yield.
[0080] The solvent used in the production of the metal complex is an alcohol, and is preferably
methanol, ethanol, isopropyl alcohol, tert-butanol, or tert-amyl alcohol. The amount
of the solvent used is not particularly limited, and is usually about 1.0 to 150 parts
by volume, preferably about 5 to 50 parts by volume, relative to 1 part by weight
of the compound represented by Formula (1).
[0081] The amount of the α-amino acid represented by Formula (5) or a salt thereof used
is not particularly limited. The amount of the α-amino acid represented by Formula
(5) or a salt thereof used may usually be about 0.1 to 10 mol, more preferably about
0.3 to 5 mol, relative to 1 mol of the compound represented by Formula (1) or a salt
thereof.
[0082] The amount of the metal compound represented by Formula (6) used is not particularly
limited. The amount of the metal compound represented by Formula (6) used may usually
be about 0.1 to 10 mol, more preferably about 0.5 to 8.0 mol, relative to 1 mol of
the compound represented by Formula (1) or a salt thereof.
[0083] Examples of the base used in the above production method include those described
for the reaction of the compound represented by Formula (7) or a salt thereof, the
compound represented by Formula (8) or a salt thereof, and the compound represented
by Formula (9) or a salt thereof. Among these, preferred are potassium carbonate,
sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, and lithium
hydroxide.
[0084] The amount of the base used is not particularly limited. The amount of the base used
may usually be about 0.1 to 20 mol, preferably 0.5 to 10 mol, relative to 1 mol of
the compound represented by Formula (1).
[0085] In the above-described production method, the reaction time of the present invention
is not particularly limited. The reaction time is usually about 0.1 to 72 hours, preferably
0.1 to 48 hours, and particularly preferably 0.1 to 20 hours.
[0086] In the above production method, the pressure for the reaction is not particularly
limited, and the reaction may be performed under any condition of atmospheric pressure,
increased pressure, and reduced pressure. The pressure for the above reaction may
usually be about 0.1 to 10 atmospheres. In this metal complex formation reaction,
the configuration of the α carbon in the amino-acid moiety of the metal complex (3)
is easily interconverted by heating. Therefore, the metal complex (3) may be once
isolated and then heated for interconversion of the configuration of the α carbon.
Alternatively, the interconversion of the configuration of the α carbon may be performed
by heating at the time of the metal complex formation.
[0087] By heating the above-produced metal complex (3) in a solvent under basic conditions,
the configuration of the α-amino acid moiety including R
9 is chirality-converted to give a metal complex represented by Formula (3'):
(wherein each sign has the same meaning as defined for the above Formula (3) ; R
10 has the same meaning as the above R
9; and ** denotes an asymmetric carbon atom).
[0088] That is, when the compound represented by Formula (1) or a salt thereof is an optical
isomer represented by Formula (1A, S-isomer):
(wherein R
1, R
2, R
3, R
4, R
5, R
6, and * have the same meanings as defined above) or a salt thereof and the α-amino
acid represented by Formula (5) or a salt thereof as a raw material is an optical
isomer of L-form, the chirality of the α-amino acid moiety of the produced metal complex
represented by Formula (3) is converted to D-form by heating under basic conditions,
but when the α-amino acid represented by Formula (5) or a salt thereof as a raw material
has a D-form configuration, the configuration of the α-amino acid moiety of the produced
metal complex represented by Formula (3) is not changed and remains in D-form.
[0089] Also, when the compound represented by Formula (1) or a salt thereof is an optical
isomer represented by Formula (1B, R-isomer):
(wherein R
1, R
2, R
3, R
4, R
5, R
6, and * have the same meanings as defined above) or a salt thereof and the α-amino
acid represented by Formula (5) or a salt thereof as a raw material is an optical
isomer of D-form, the chirality of the α-amino acid moiety of the produced metal complex
represented by Formula (3) is converted to L-form by heating under basic conditions,
but when the α-amino acid represented by Formula (5) or a salt thereof as a raw material
has an L-form configuration, the configuration of the α-amino acid moiety of the produced
metal complex represented by Formula (3) is not changed and remains in L-form.
[0090] Thus, the production method is characterized in that, by using an appropriately selected
optical isomer of an N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]ac etamide
compound, the configuration of the α-amino acid moiety is converted. That is, the
production method include a method for producing, by using an α-amino acid represented
by Formula (5) having a configuration of L-form as a raw material, a metal complex
represented by Formula (3') in which the configuration of the α-carbon in the α-amino
acid moiety including R
10 is converted to D-form; and a method for producing, by using an α-amino acid represented
by Formula (5) having a configuration of D-form as a raw material, a metal complex
represented by Formula (3') in which the configuration of the α-carbon in the α-amino
acid moiety including R
10 is converted to L-form.
[0091] Further, in the production method, by using an appropriately selected optical isomer
of an N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl] acetamide compound
and by using a racemic mixture of an α-amino acid represented by Formula (5) as a
raw material, a metal complex represented by Formula (3') in which the configuration
of the α-amino acid moiety including R
10 is converted to either L-form or D-form can be produced.
[0092] The solvent used in the chirality conversion is an alcohol or the like, and is preferably
methanol, ethanol, isopropyl alcohol, tert-butanol, tert-amyl alcohol or methyl isobutyl
ketone. The amount of the solvent used is not particularly limited, and is usually
about 1.0 to 150 parts by volume, preferably about 5 to 50 parts by volume, relative
to 1 part by weight of the compound represented by Formula (1).
[0093] In the chirality interconversion, the configuration of the α carbon in the α-amino-acid
moiety of the metal complex represented by Formula (3) is converted by heating an
alcohol solution of the metal complex usually at about 40 to 80°C for about 0.5 to
24 hours.
[0094] The pressure for the reaction is not particularly limited, and the reaction may be
performed under any condition of atmospheric pressure, increased pressure, and reduced
pressure. The pressure for the above reaction may usually be about 0.1 to 10 atmospheres.
(Separation and purification)
[0095] In the above-described production method, an optically pure objective substance can
be obtained by performing a known separation and/or purification method after the
reaction. Examples of the means therefor include solvent exchange, concentration,
chromatography, crystallization, distillation, etc., for example.
[0096] Next, a method of acid decomposition for releasing a chiral α-amino acid represented
by Formula (5') from the metal complex represented by Formula (3') in which the chirality
of the α-amino acid moiety has been converted will be described below. The metal complex
represented by Formula (3'):
(wherein each sign has the same meaning as defined for the above Formula (3) ; R
10 has the same meaning as the above R
9; and ** denotes an asymmetric carbon atom) in which the chirality of the α-amino
acid moiety has been converted is reacted with an acid for acid decomposition of the
compound represented by Formula (3') or a salt thereof, an α-amino acid represented
by Formula (5'):
(wherein R
10 has the same meaning as the above R
9; ** denotes an asymmetric carbon atom; and the configuration of the α carbon is converted
from the compound represented by Formula (5)) having a desired chirality or a salt
thereof can be produced.
[0097] The configuration of the α-amino acid represented by Formula (5') or a salt thereof
is the same as that of the α-amino acid moiety of the metal complex represented by
Formula (3').
[0098] The acid used for the above-described production method is not particularly limited,
and any known acid may be used. The acid may be an inorganic acid or an organic acid.
Examples of the inorganic acid include hydrochloric acid, nitric acid, sulfuric acid,
perchloric acid, etc. Examples of the organic acid include acetic acid, trifluoroacetic
acid, methanesulfonic acid, trifluoromethanesulfonic acid, oxalic acid, propionic
acid, butanoic acid, valeric acid, etc. Preferred are hydrochloric acid, sulfuric
acid, trifluoroacetic acid, and methanesulfonic acid, and more preferred are hydrochloric
acid and methanesulfonic acid.
[0099] Preferable reaction conditions for the acid decomposition of the metal complex represented
by Formula (3') will be shown below.
[0100] The amount of the acid used is not particularly limited. The amount of the acid used
may usually be about 0.1 to 20 mol, preferably about 0.3 to 10 mol, relative to 1
mol of the metal complex represented by Formula (3'), for example.
[0101] The solvent used in the production method is preferably an alcohol, and is more preferably
methanol or ethanol. The amount of the solvent used may usually be about 0.1 to 100
parts by volume, preferably 0.5 to 50 parts by volume, relative to 1 part by weight
of the metal complex represented by Formula (3'), for example.
[0102] In the above-described production method, the reaction temperature is usually about
0 to 100°C, preferably 0 to 80°C, more preferably 5 to 60°C, and particularly preferably
40 to 60°C.
[0103] In the above-described production method, the reaction time is usually about 0.1
to 72 hours, preferably about 0.1 to 48 hours, and particularly preferably about 0.1
to 20 hours.
[0104] The pressure for the above reaction is not particularly limited, and may be about
0.1 to 10 atmospheres, for example.
(Separation and purification)
[0105] In the above-described production method, an optically pure objective substance can
be obtained by performing a known separation and/or purification method after the
reaction.
(Product)
[0106] By the above production method, an α-amino acid represented by Formula (5'):
(wherein each sign has the same meaning as defined for the above Formula (5')) having
any chirality or a salt thereof can be produced. Examples of the α-amino acid represented
by Formula (5') include those listed for the above Formula (5), for example. However,
the configuration of the α carbon of the α-amino acid represented by Formula (5')
or a salt thereof is converted from the α-amino acid represented by Formula (5) or
a salt thereof.
Examples
(HPLC measurement conditions)
[0107] In Examples and Reference Examples, measurements were made under the following HPLC
conditions.
<HPLC conditions-1: complex analysis conditions>
[0108] Column: Inertsil™ ODS-3 (3 µm, 150 × 4.6 mm i.d.)
Eluent: A:B = 40:60 to 20:80 (0 to 25 min) and
20:80 (25 min to 45 min)
A = 10 mM ammonium formate in 0.1% formic acid buffer solution
B = acetonitrile
Flow rate: 1.0 mL/min
Temp: 40°C
Detector: UV 254 nm
<HPLC conditions-2: Z-Phe chiral analysis conditions 1>
[0109] Column: CHIRALCELL OJ-RH (5 µm, 150 × 4.6 mm i.d.)
Eluent: A:B = 65:35 (0 to 30 min)
A = 0.1% phosphoric acid aqueous solution
B = acetonitrile containing 0.1% phosphoric acid
Flow rate: 0.5 mL/min
Temp: 35°C
Detector: UV 200 nm
<HPLC conditions-2': Z-Phe chiral analysis conditions 2>
[0110] Column: CHIRALCELL OJ-RH (5 µm, 150 × 4.6 mm i.d.)
Eluent: A:B = 65:35 (0 to 30 min)
A = 0.1% phosphoric acid aqueous solution
B = acetonitrile containing 0.1% phosphoric acid
Flow rate: 0.5 mL/min
Temp: 35°C
Detector: UV 254 nm
<HPLC conditions-3: Gln complex analysis conditions>
[0111] Column: Inertsil™ ODS-3 (3 µm, 150 × 4.6 mm i.d.)
Eluent: A:B = 40:60 (0 to 40 min) and 10:90 (41 min to 50 min)
A = 10 mM ammonium formate in 0.1% formic acid buffer solution
B = acetonitrile
Flow rate: 0.5 mL/min
Temp: 40°C
Detector: UV 254 nm
<HPLC conditions-4: Z-D-Lys(Z) chiral analysis conditions>
[0112] Column: CHIRALPAK AS-RH (5 µm, 150 × 4.6 mm i.d.)
Eluent: A:B = 60:40 (0 to 12 min)
A = phosphoric acid aqueous solution (pH = 2)
B = acetonitrile
Flow rate: 1.0 mL/min
Temp: 25°C
Detector: UV 200 nm
Example 1. Synthesis of chiral template (chiral auxiliary) Example 1-1: Synthesis
of
(S)-N-(2-benzoylphenyl)-2-[3,5-dihydro-4H-dinaphtho [2,1-c:1',2'-e]azepin-4-yl]acetamide
[0113]
[0114] To an acetonitrile solution (40 mL) of N-(2-benzoylphenyl)-2-bromoacetamide (2.0
g, 6.3 mmol), potassium carbonate (1.74 g, 12.58 mmol) and (S)-binaphthyl amine were
added. The mixture was heated to 40°C and stirred for 17 hours. After the end of the
reaction, the reaction suspension was concentrated to dryness. The concentrated residue
was purified by silica gel chromatography (n-hexane:ethyl acetate = 4:1(v/v)) to give
(S)-N-(2-benzoylphenyl)-2-[3,5-dihydro-4H-dinaphtho[2,1-c:1 ',2'-e]azepin-4-yl]acetamide
(3.14 g, yield: 93.8%, purity: 99.1%) as pale yellow crystals.
ESI-MS (positive mode): m/z = 533.3 for [M + H]
+.
1H-NMR (200 MHz, CDCl
3) : δ 3.10 and 3.57 (1H each, ABq, J = 16.7 Hz, COCH
2), 3.40 and 3.66 (2H each, ABq, J = 12.3 Hz, 2 × NCH
2) , 7.13 (1H, ddd, J = 7.9, 7.3, 1.1 Hz, ArH), 7.26 (1H, ddd, J = 8.8, 6.4, 1.3 Hz,
ArH), 7.42-7.63 (12H, m, ArH), 7.74-7.80 (2H, m, ArH), 7.92-7.98 (2H, m, ArH), 7.94
(2H, d, J = 8.2 Hz, ArH), 8.64 (1H, dd, J = 8.4, 0.7 Hz, ArH), 11.59 (1H, br s, NH).
13C-NMR (50.3 MHz, CDCl
3) : δ 56.4 (CH
2), 60.5 (CH
2), 122.0 (ArCH), 122.5 (ArCH), 125.6 (ArCH), 125.8 (ArCH), 127.5 (ArCH), 127.7 (ArCH),
128.3 (ArCH), 128.6 (ArCH), 130.2 (ArCH), 131.5 (quaternary ArC), 132.5 (ArCH), 132.6
(ArCH), 133.2 (quaternary ArC), 133.3 (quaternary ArC), 133.4 (ArCH), 135.0 (quaternary
ArC), 138.5 (quaternary ArC), 139.0 (quaternary ArC), 170.2 (CO), 197.8 (CO).
Example 1-2: Synthesis of (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide
[0115]
[0116] To an acetonitrile solution (500 mL) of 2-amino-5-chlorobenzophenon (25.0 g, 107.9
mmol), potassium carbonate (44.7 g, 323.7 mmol) and a solution (50 mL)of bromoacetyl
bromide (28.3 g, 140.3 mmol) in acetonitrile were added. The mixture was stirred at
room temperature for 0.5 hour. After the end of the reaction, the precipitate was
filtered off, and the filtrate was concentrated to dryness. To the concentrated residue,
city water (75 mL) was added, and phase separation was performed with ethyl acetate
(200 mL, twice). The organic layers were washed with city water (150 mL), dried over
sodium sulfate, and then concentrated to 150 mL. To the concentrated liquid, n-hexane
(50 mL) was added, and the mixture was stirred at room temperature for 16 hours and
subsequently at 0°C for 1 hour. The precipitated crystals were separated by filtration,
and then dried under vacuum at 30°C to give N-(2-benzoyl-4-chlorophenyl)-2-bromoacetamide
(33.16 g, yield: 87%, purity: 99.2%) as slightly white crystals.
1H-NMR (200 MHz, CDCl
3) : δ 4.02 (2H, s, COCH
2), 7.48-7.76 (7H, m, ArH), 8.55-8.60 (1H, m, ArH), 11.32 (1H, br s, NH).
[0117] To an acetonitrile solution (60 mL) of N-(2-benzoyl-4-chlorophenyl)-2-bromoacetamide
(2.0 g, 5.7 mmol), potassium carbonate (1.18 g, 8.5 mmol) and (S) -binaphthyl amine
were added. The mixture was heated to 40°C and stirred for 16 hours. After the end
of the reaction, the reaction suspension was concentrated to dryness. The concentrated
residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 4:1(v/v))
to give (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth o[2,1-c:1',2'-e]azepin-4-yl]acetamide
(3.25 g, yield: quantitative, purity: 99.7%, 99.8%ee) as pale yellow crystals. ESI-MS
(positive mode): m/z = 567.2 for [M + H]
+.
1H-NMR (200 MHz, CDCl
3) : δ 3.09 and 3.54 (1H each, ABq, J = 16.8 Hz, COCH
2), 3.39 and 3.61 (2H each, ABq, J = 12.1 Hz, 2 × NCH
2), 7.21-7.30 (2H, m, ArH), 7.42-7.65 (11H, m, ArH), 7.73-7.80 (2H, m, ArH), 7.92-7.98
(2H, m, ArH), 7.94 (2H, d, J = 8.2 Hz, ArH), 8.62 (2H, d, J = 8.6 Hz, ArH), 11.49
(1H, br s, NH).
13C-NMR (50.3 MHz, CDCl
3) : δ 56.4 (CH
2), 60.3 (CH
2), 123.3 (ArCH), 125.6 (ArCH), 125.9 (ArCH), 126.8 (quaternary ArC), 127.5 (ArCH),
127.6 (ArCH), 127.8 (quaternary ArC), 127.9 (quaternary ArC), 128.3 (ArCH), 128.6
(ArCH), 128.7 (ArCH), 130.2 (ArCH), 131.4 (quaternary ArC), 131.6 (ArCH), 133.1 (ArCH),
133.3 (quaternary ArC), 135.0 (quaternary ArC), 137.4 (quaternary ArC), 137.6 (quaternary
ArC), 170.2 (CO), 196.4 (CO).
Example 2. Inversion
Example 2-1: Synthesis of D-phenylalanine by chiral inversion of L-phenylalanine:
Synthesis of nickel complex having D-phenylalanine moiety
[0118]
[0119] To a methanol suspension (4 mL) of (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.2 g, 0.353 mmol), nickel acetate tetrahydrate
(0.176 g, 0.706 mmol), L-phenylalanine (0.117 g, 0.706 mmol), and potassium carbonate
(0.293 g, 2.118 mmol) were added, and the mixture was refluxed for 24 hours. After
the end of the reaction, the reaction mixture was added to an ice-cooled 5% acetic
acid aqueous solution (15 mL) and stirred for 30 minutes to allow crystals to precipitate.
The crystals were separated by filtration, and then blow-dried at 50°C to give a nickel
(II) complex having a D-phenylalanine moiety (0.246 g, yield: 90.5%, 98% de) as red
crystals.
[0120] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 1.
Example 2-2: Synthesis of L-phenylalanine by chiral inversion of D-phenylalanine:
Synthesis of nickel complex having L-phenylalanine moiety
[0121]
[0122] To a methanol suspension (4 mL) of (R)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.4 g, 0.705 mmol), nickel acetate tetrahydrate
(0.351 g, 1.411 mmol), D-phenylalanine (0.233 g, 1.411 mmol), and potassium carbonate
(0.585 g, 4.232 mmol) were added, and the mixture was refluxed for 24 hours. After
the end of the reaction, the reaction mixture was added to an ice-cooled 5% acetic
acid aqueous solution (60 mL) and stirred for 30 minutes to allow crystals to precipitate.
The crystals were separated by filtration, and then blow-dried at 50°C to give a nickel
(II) complex having an L-phenylalanine moiety (0.493 g, yield: 90.6%, 97% de) as red
crystals.
[0123] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 2.
Example 2-3: Synthesis of D-leucine by chiral inversion of L-leucine: Synthesis of
nickel complex having D-leucine moiety
[0124]
[0125] To a methanol suspension (2 mL) of (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.1 g, 0.176 mmol), nickel acetate tetrahydrate
(0.088 g, 0.353 mmol), L-leucine (0.046 g, 0.353 mmol), and potassium carbonate (0.146
g, 1.058 mmol) were added, and the mixture was refluxed for 25 hours. After the end
of the reaction, the reaction mixture was added to an ice-cooled 5% acetic acid aqueous
solution (15 mL) and stirred for 30 minutes to allow crystals to precipitate. The
crystals were separated by filtration, and then vacuum-dried at 40°C to give a nickel
(II) complex having a D-leucine moiety (0.116 g, yield: 89.1%, 91.6% de) as red crystals.
ESI-MS (positive mode): m/z = 736.3 for [M + H]
+.
1H-NMR (200 MHz, CDCl
3): δ 0.43 (3H, d, J = 6.4 Hz, Me), 0.87 (3H, d, J = 6.6 Hz, Me), 1.28 (1H, ddd, J
= 13.3, 10.1, 3.7 Hz, one of β-CH
2 of Leu part), 1.88-2.05 (1H, m, CHMe
2), 2.34 (1H, ddd, J = 13.3, 10.5, 3.5 Hz, one of β-CH
2 of Leu part), 2.72 [1H, d, J = 12.1 Hz, one of azepine C(α)H
2N], 3.07 [1H, d, J = 15.6 Hz, one of azepine C(α) H
2N], 3.67 and 3.73 (1H each, ABq, J = 13.9 Hz, acetanilide NCOCH
2), 3.81 (1H, dd, J = 10.1, 3.5 Hz, α-H of Leu part), 4.56 [1H, d, J = 15.6 Hz, one
of azepine C(α')H
2N], 4.83 [1H, d, J = 12.1 Hz, one of azepine C(α) H
2N], 6.66 (1H, d, J=2.4Hz, ArH), 6.89-6.97 (1H, m, ArH), 7.18-7.58 (12H, m, ArH), 7.94-8.03
(3H, m, ArH), 8.16 (1H, d, J = 8.2 Hz, ArH), 8.42 (1H, d, J = 9.2 Hz, ArH), 8.77 (1H,
d, J = 8.2 Hz, ArH).
13C-NMR (50.3 MHz, CDCl
3) : δ 20.8 and 23.8 (2 × Me of Leu part), 24.3 (γ-CH of Leu part), 45.4 (β-CH
2 of Leu part), 58.8 (NCOCH
2), 61.9 and 66.4 (2 × CH
2 of azepine), 69.4 (α-CH of Leu part), 125.1 (ArCH), 126.1 (quaternary ArC), 126.37
(ArCH), 126.44 (ArCH), 127.3 (ArCH), 127.4 (ArCH), 127.5 (ArCH), 127.8 (ArCH), 127.9
(ArCH), 128.4 (ArCH), 128.66 (ArCH), 128.73 (quaternary ArC), 129.17 (ArCH), 129.24
(ArCH), 129.5 (ArCH), 130.3 (ArCH), 131.0 (quaternary ArC), 131.2 (quaternary ArC),
131.5 (quaternary ArC), 132.4 (ArCH), 132.5 (ArCH), 132.8 (quaternary ArC), 133.7
(quaternary ArC), 134.1 (quaternary ArC), 135.6 (quaternary ArC), 136.0 (quaternary
ArC), 140.9 (quaternary ArC), 169.5, 174.6, 178.5 (CN and 2 × CO).
[0126] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 3.
Example 2-4: Synthesis of D-methionine by chiral inversion of L-methionine: Synthesis
of nickel complex having D-methionine moiety
[0127]
[0128] To a methanol suspension (1 mL) of (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.1 g, 0.176 mmol), nickel chloride (0.0457
g, 0.353 mmol), L-methionine (0.053 g, 0.352 mmol), and potassium carbonate (0.146
g, 1.057 mmol) were added, and the mixture was refluxed for 2 hours. After the end
of the reaction, the reaction mixture was added to an ice-cooled 5% acetic acid aqueous
solution (20 mL) and stirred for 30 minutes to allow crystals to precipitate. The
crystals were separated by filtration, and then vacuum-dried at 50°C to give a nickel
(II) complex having a D-methionine moiety (0.129 g, yield: 97.2%, 93.3% de) as red
crystals.
ESI-MS (positive mode): m/z = 754.3 for [M + H]
+.
1H-NMR (200 MHz, CDCl
3) : δ 1.82-2.15 (2H, m, β-CH
2 of Met part), 2.12 (3H, s, SMe), 2.70 [1H, d, J = 12.3 Hz, one of azepine C(α) H
2N], 2.76 (1H, dt, J = 13.4, 7.0 Hz, one of γ-CH
2 of Met part), 3.05 [1H, d, J = 15.6 Hz, one of azepine C(α')H
2N], 3.24 (1H, ddd, J = 13.4, 8.1, 6.3 Hz, one of γ-CH
2 of Met part), 3. 67 and 3.74 (1H each, ABq, J = 14.0 Hz, acetanilide NCOCH
2), 3. 97 (1H, dd, J = 6.8, 4.0 Hz, α-H of Met part), 4.55 [1H, d, J = 15.6 Hz, one
of azepine C(α')H
2N], 4.84 [1H, d, J = 12.3 Hz, one of azepine C(α) H
2N], 6.64 (1H, d, J = 2.4 Hz, ArH), 6.90-6.98 (1H, m, ArH), 7.12-7.19 (1H, m, ArH),
7.22-7.59 (11H, m, ArH), 7.95-8.03 (3H, m, ArH), 8.16 (1H, d, J = 8.2 Hz, ArH), 8.43
(1H, d, J = 9.2 Hz, ArH), 8.80 (1H, d, J = 8.2 Hz, ArH).
13C-NMR (50.3 MHz, CDCl
3) : δ 15.7 (Me), 29.8 (CH
2), 33.2 (CH
2), 58.7 (NCOCH
2), 61.8 and 66.5 (2 × CH
2 of azepine), 69.8 (α-CH of Glu part), 125.2 (ArCH), 126.1 (quaternary ArC), 126.37
(quaternary ArC), 126.44 (ArCH), 126.9 (ArCH), 127.3 (ArCH), 127.5 (ArCH), 127.9 (ArCH),
128.4 (ArCH), 128.6 (ArCH), 128.7 (quaternary ArC), 129.2 (ArCH), 129.37 (ArCH), 129.42
(ArCH), 130.4 (ArCH), 131.0 (quaternary ArC), 131.2 (quaternary ArC), 131.5 (quaternary
ArC), 132.4 (ArCH), 132.7 (ArCH), 132.9 (quaternary ArC), 133.7 (quaternary ArC),
134.0 (quaternary ArC), 135.5 (quaternary ArC), 136.0 (quaternary ArC), 141.2 (quaternary
ArC), 170.2, 174.6, 178.0 (CN and 2 × CO).
[0129] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 4.
Example 2-5: Synthesis of D-tryptophan by chiral inversion of L-tryptophan: Synthesis
of nickel complex having D-tryptophan moiety
[0130]
[0131] To a methanol suspension (10 mL) of (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.5 g, 0.882 mmol), nickel acetate tetrahydrate
(0.360g, 1.763 mmol), L-tryptophan (0.439 g, 1.763 mmol), and potassium carbonate
(0.731 g, 5.290 mmol) were added, and the mixture was refluxed with stirring for 24
hours. After the end of the reaction, the reaction mixture was added to an ice-cooled
5% acetic acid aqueous solution (70 mL) and stirred for 30 minutes to allow crystals
to precipitate. The crystals were separated by filtration, and then vacuum-dried at
50°C to give a nickel (II) complex having a D-tryptophan moiety (0.602 g, yield: 84.3%,
99.4% de) as red crystals.
ESI-MS (positive mode): m/z = 809.2 for [M + H]
+.
1H-NMR (200 MHz, CDCl
3) : δ 1.52 (1H, d, J = 14.1 Hz, one of acetanilide NCOCH
2), 2.25 [1H, d, J = 12.1 Hz, one of azepine C(α)H
2N], 2.34 [1H, d, J = 15.6 Hz, one of azepine C(α')H
2N], 2.74 (1H, H
A of ABX type, J
AB = 14.4 Hz, J
AX = 5.7 Hz, one of AA β-CH
2), 2.81 (1H, d, J = 14.1 Hz, one of acetanilide NCOCH
2), 3.04 [1H, d, J = 15.6 Hz, one of azepine C(α')H
2N], 3.30 (1H, H
B of ABX type, J
AB = 14.4 Hz, J
BX = 2.2 Hz, one of AA β-CH
2)' 4.16 (1H, H
X of ABX type, J
AX = 5.7 Hz, J
BX = 2.2 Hz, α-H of AA part), 4.43 [1H, d, J
= 12.1 Hz, one of azepine C(α) H
2N], 6.68 (1H, d, J = 2.6 Hz, ArH), 6.99 (1H, d, J = 2.2 Hz, ArH), 7.02-7.63 (15H,
m, ArH), 7.74-7.81 (2H, m, ArH), 7.85-7.94 (3H, m, ArH), 8.06 (1H, d, J = 8.4 Hz,
ArH), 8.26 (1H, d, J = 9.0 Hz, ArH), 8.66 (1H, d, J = 8.2 Hz, ArH), 9.11 (1H, br d,
J = 1.8 Hz, NH).
13C-NMR (50.3 MHz, CDCl
3) : δ 29.7 (β-CH
2 of Phe part), 56.5 (NCOCH
2), 61.4 and 65.0 (2 × CH
2 of azepine), 71.8 (α-CH of AA part), 110.4 (ArCH), 111.2 (ArCH), 120.7 (ArCH), 121.1
(ArCH), 122.9 (ArCH), 125.2 (ArCH), 125.5 (ArCH), 126.1 (quaternary ArC), 126.2 (ArCH),
126.3 (ArCH), 127.1 (ArCH), 127.2 (ArCH), 127.4 (ArCH), 127.7 (ArCH), 128.3 (ArCH),
128.4 (ArCH), 128.7 (ArCH), 128.9 (quaternary ArC), 129.0 (quaternary ArC), 129.1
(ArCH), 129.4 (ArCH), 130.4 (ArCH), 130.9 (quaternary ArC), 131.0 (quaternary ArC),
131.3 (quaternary ArC), 132.3 (ArCH), 132.4 (ArCH), 132.8 (quaternary ArC), 133.4
(quaternary ArC), 133.9 (quaternary ArC), 135.2 (quaternary ArC), 135.8 (quaternary
ArC), 136.8 (quaternary ArC), 141.0 (quaternary ArC), 169.2, 174.6, 178.8 (CN and
2 × CO).
[0132] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 5.
Example 2-6: Synthesis of D-glutamine by chiral inversion of L-glutamine: Synthesis
of nickel complex having D-glutamine moiety
[0133]
[0134] To a methanol suspension (2 mL) of (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.1 g, 0.176 mmol), nickel acetate tetrahydrate
(0.0878g, 0.353 mmol), L-glutamine (0.052 g, 0.353 mmol), and a 28% solution of sodium
methoxide (0.204 g, 1.058 mmol) in methanol were added, and the mixture was refluxed
for 1 hour and then stirred at 40°C for 1 hour. After the end of the reaction, the
reaction mixture was added to an ice-cooled 5% acetic acid aqueous solution (15 mL)
and stirred for 1 hour to allow crystals to precipitate. The crystals were separated
by filtration, and then vacuum-dried at 40°C to give a nickel (II) complex having
a D-glutamine moiety (0.116 g, yield: 87.3%, 94.2% de) as red crystals.
ESI-MS (positive mode): m/z = 752.0 for [M + H]
+.
1H-NMR (200 MHz, CDCl
3): δ 1.68-1.88 (1H, m), 2.09-2.25 (1H, m), 2.34-2.70 (2H, m), 2.72 [1H, d, J = 12.2
Hz, one of azepine C(α) H
2N], 3.00 [1H, d, J = 15.6 Hz, one of azepine C(α')H
2N], 3.62 and 3.73 (1H each, ABq, J = 13.7 Hz, acetanilide NCOCH
2), 3.79 (1H, dd, J = 8.7, 4.3 Hz, α-H of Gln part), 4.56 [1H, d, J = 15.6 Hz, one
of azepine C(α')H
2N], 4.84 [1H, d, J = 12.2 Hz, one of azepine C(α) H
2N], 5.20 (1H, br s, one of CONH
2), 6.38 (1H, br s, one of CONH
2), 6.66 (1H, d, J = 2.4 Hz, ArH), 6.94-7.01 (1H, m, ArH), 7.13-7.20 (1H, m, ArH),
7.21-7.33 (3H, m, ArH), 7.37-7.59 (8H, m, ArH), 7.86-8.01 (3H, m, ArH), 8.15 (1H,
d, J = 8.2 Hz, ArH), 8.45 (1H, d, J = 9.2 Hz, ArH), 8.74 (1H, d, J = 8.4 Hz, ArH).
13C-NMR (50.3 MHz, CDCl
3) : δ 30.2 (CH
2), 31 .2 (CH
2), 58.4 (NCOCH
2), 61.9 and 66.2 (2 x CH
2 of azepine), 69.8 (α-CH of Gln part), 125.2 (ArCH), 126.1 (quaternary ArC), 126.5
(ArCH), 126.6 (ArCH), 127.3 (ArCH), 127.5 (ArCH), 127.8 (ArCH), 128.0 (ArCH), 128.1
(quaternary ArC), 128.4 (ArCH), 128.6 (ArCH), 128.8 (quaternary ArC), 129.0 (ArCH),
129.1 (ArCH), 129.3 (ArCH), 129.5 (ArCH), 130.3 (ArCH), 131.1 (quaternary ArC), 131.2
(quaternary ArC), 131.4 (quaternary ArC), 132.6 (ArCH), 132.7 (ArCH), 133.6 (quaternary
ArC), 133.9 (quaternary ArC), 135.5 (quaternary ArC), 136.1 (quaternary ArC), 141.0
(quaternary ArC), 170.7, 173.6, 174.8, 178.5 (CN and 3 × CO).
[0135] The product of this Example was analyzed under HPLC conditions-3: Gln complex analysis
conditions. The results are shown in Fig. 6.
Example 2-7: Synthesis of D-glutamic acid by chiral inversion of L-glutamic acid:
Synthesis of nickel complex having D-glutamic acid moiety
[0136]
[0137] To a methanol suspension (2 mL) of (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.1 g, 0.176 mmol), nickel acetate tetrahydrate
(0.878 g, 0.353 mmol), L-glutamic acid (0.052 g, 0.353 mmol), and potassium carbonate
(0.195 g, 1.411 mmol) were added. To this, methanol (2 mL) was further added, and
the mixture was stirred at 60°C for 9 hours. After the end of the reaction, the reaction
mixture was added to an ice-cooled 5% acetic acid aqueous solution (15 mL) and stirred
for 1 hour to allow crystals to precipitate. The crystals were separated by filtration,
and then vacuum-dried at 40°C to give a nickel (II) complex having a D-glutamic acid
moiety (0.110 g, yield: 82.5%, 91.8% de (determined based on
1H-NMR spectrum)) as red crystals.
ESI-MS (positive mode): m/z = 752.0 for [M + H]
+.
1H-NMR (200 MHz, CDCl
3) : δ 1.60-1.78 (1H, m, one of β-CH
2 of Glu part), 1.90-2.10 (1H, m, one of β-CH
2 of Glu part), 2.50-2.70 (1H, m, one of γ-CH
2 of Glu part), 2.64 [1H, d, J = 12.1 Hz, one of azepine C(α) H
2N], 2.95 [1H, d, J = 15.6 Hz, one of azepine C(α')H
2N], 3.20-3.41 (1H, m, one of γ-CH
2 of Glu part), 3.67 and 3.81 (1H each, ABq, J = 13.8 Hz, acetanilide NCOCH
2), 3.94 (1H, br t-like, α-H of Glu part), 4.5-5.1 (1H, br, CO
2H), 4.77 [1H, d, J = 15.6 Hz, one of azepine C(α')H
2N], 4.78 [1H, d, J = 12.1 Hz, one of azepine C(α) H
2N], 6.58 (1H, d, J = 2.6 Hz, ArH), 6.98-7.64 (12H, m, ArH), 7.61 (1H, d, J = 8.2 Hz,
ArH), 7.91-8.01 (3H, m, ArH), 8.14 (1H, d, J = 8.4 Hz, ArH), 8.28 (1H, d, J = 9.2
Hz, ArH), 8.78 (1H, d, J = 8.4 Hz, ArH).
13C-NMR (50.3 MHz, CDCl
3) : δ 27.4 (CH
2), 30.4 (CH
2), 58.5 (NCOCH
2), 61.8 and 66.5 (2 × CH
2 of azepine), 70.4 (α-CH of Glu part), 125.2 (ArCH), 126.1 (quaternary ArC), 126.37
(ArCH), 126.44 (ArCH), 126.6 (ArCH), 127.5 (ArCH), 127.6 (ArCH), 127.8 (ArCH), 128.0
(ArCH), 128.37 (quaternary ArC), 128.44 (ArCH), 128.7 (ArCH), 129.0 (ArCH), 129.1
(ArCH), 129.2 (ArCH), 129.4 (ArCH), 130.2 (ArCH), 131.1 (quaternary ArC), 131.2 (quaternary
ArC), 131.5 (quaternary ArC), 132.5 (ArCH), 132.9 (quaternary ArC), 133.7 (quaternary
ArC), 134.0 (quaternary ArC), 135.4 (quaternary ArC), 136.1 (quaternary ArC), 140.8
(quaternary ArC), 171.5, 175.7, 176.2, 178.3 (CN and 3 × CO).
[0138] In the
1H-NMR of the product of this Example, the signals at chemical shift values (multiplicity,
coupling constant) of 6.58 ppm (d, J = 2.6 Hz) and 6.66 ppm (d, J = 2.6 Hz) correspond
to the proton signals of the aromatic rings of nickel (II) complexes having a D-glutamic
acid moiety and an L-glutamic acid moiety, respectively, and the integrated intensity
ratio was 9.32:0.40 (= 95.9:4.1). Based on the results, the diastereomer excess (de)
was determined to be 91.8%. The
1H-NMR spectrum of the product of this Example is shown in Fig. 7.
Example 2-8: Synthesis of D-lysine by chiral inversion of L-lysine: Synthesis of nickel
complex having D-lysine moiety
[0139]
[0140] To a methanol suspension (2 mL) of (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.3 g, 0.529 mmol), nickel acetate tetrahydrate
(0.263 g, 1.058 mmol), L-lysine hydrochloride (1.193 g, 1.508 mmol), and potassium
carbonate (0.585 g, 4.232 mmol) were added, and the mixture was refluxed for 4 hours.
After the end of the reaction, dichloromethane (5 mL) and a 5% acetic acid aqueous
solution (5 mL) were added to the reaction mixture, and phase separation was performed.
To the organic layer, dichloromethane and methanol were added, and the liquid was
washed with water (5 mL) and then with saturated brine (5 mL). The organic layer was
concentrated, and the residue was washed with stirring in dichloromethane (1 mL) and
ethyl acetate (6 mL). The crystals were separated by filtration, and then blow-dried
at 50°C to give a nickel (II) complex having a D-lysine moiety (0.323 g, yield: 81.2%)
as a red solid.
ESI-MS (positive mode): m/z = 751.2 for [M + H]
+.
1H-NMR (200 MHz, CDCl
3) : δ 1.20-1.80 (4H, m), 1.82-2.02 (1H, m), 2.23-2.43 (1H, m), 2.52-2.78 (1H, br),
2.72 [1H, d, J = 12.3 Hz, one of azepine C(α) H
2N], 3.04 [1H, d, J = 15.6 Hz, one of azepine C(α')H
2N], 3.27 (3H, br, NH
2 and one of CH
2), 3.66 and 3.83 (1H each, ABq, J = 13.6 Hz, acetanilide NCOCH
2), 3.82 (1H, H
X of ABX system, overlapped, α-H of Lys part), 4.73 [1H, d, J = 15.6 Hz, one of azepine
C(α')H
2N], 4.80 [1H, d, J = 12.3 Hz, one of azepine C(α) H
2N], 6.64 (1H, d, J = 2.6 Hz, ArH), 6.84-6.91 (1H, m, ArH), 7.14-7.56 (11H, m, ArH),
7.61 (1H, d, J = 8.2 Hz, ArH), 7.90-8.00 (3H, m, ArH), 8.14 (1H, d, J = 8.2 Hz, ArH),
8.42 (1H, d, J = 9.2 Hz, ArH), 8.75 (1H, d, J = 8.2 Hz, ArH).
13C-NMR (50.3 MHz, CDCl
3) : δ 22.6 (γ-CH
2), 30.9 (δ-CH
2), 34.6 (β-CH
2), 40.6 (ε-CH
2), 58.5 (NCOCH
2), 61.8 and 66.3 (2 × CH
2 of azepine), 70.6 (α-CH of Lys part), 125.2 (ArCH), 126.2 (quaternary ArC), 126.3
(quaternary ArC), 126.4 (ArCH), 127.0 (ArCH), 127.5 (ArCH), 127.9 (ArCH), 128.4 (ArCH),
128.7 (ArCH), 128.9 (quaternary ArC), 129.17 (ArCH), 129.24 (ArCH), 129.4 (ArCH),
130.3 (ArCH), 131.1 (quaternary ArC), 131.2 (quaternary ArC), 131.4 (quaternary ArC),
132.4 (ArCH), 132.6 (ArCH), 132.8 (quaternary ArC), 133.7 (quaternary ArC), 134.0
(quaternary ArC), 135.5 (quaternary ArC), 136.0 (quaternary ArC), 141.0 (quaternary
ArC), 170.0, 174.8, 178.5 (CN and 2 × CO).
Example 3-1: Release of L-phenylalanine from nickel (II) complex having L-phenylalanine
moiety (obtained by deracemization of racemic mixture of phenylalanine or by chiral
inversion of D-phenylalanine) in acid condition, and protection of L-phenylalanine
with Z-group
[0141]
[0142] To a methanol suspension (12 mL) of a nickel (II) complex having an L-phenylalanine
moiety (0.4 g, 0.52 mmol), 1 N hydrochloric acid (2.6 mL, 5 eq.) was added, and the
mixture was stirred at 40°C for 6 hours. After the end of the reaction, the reaction
mixture was concentrated, and the residue was dissolved in dichloromethane (10 mL).
The organic layer was extracted with 2% aqueous ammonia (6 mL, twice) and water (6
mL, twice) and then washed with saturated brine (6 mL, twice). The obtained organic
layer was dried over sodium sulfate, and the sodium sulfate was filtered off. The
filtrate was concentrated to dryness to give a chiral auxiliary (0.27 g, yield: 90%)
as a pale yellow solid.
[0143] The aqueous ammonia layers and the aqueous layers resulting from the extraction were
combined and concentrated to dryness. The obtained solid was dissolved in 9% aqueous
ammonia (3 mL) and passed through a cation exchange resin column (made by Mitsubishi
Chemical Corp., trade name: SK1B, 9 mL, eluent: water and subsequently aqueous ammonia
2% → 8%)) to give phenylalanine (0.083 g, crude product).
[0144] To the phenylalanine (0. 078 g), an aqueous solution (3 mL) of sodium hydrogencarbonate
(0.041 mg, 1 eq.)-sodium carbonate (0.103 mg, 2 eq.), and acetone (1 mL) were added
to dissolve the phenylalanine. To the solution in an ice bath, an acetone solution
(1 mL) of N-benzyloxycarbonyloxy succinimide (0.121 g, 1 eq.) was added, and the mixture
was stirred at room temperature for 3 hours. The reaction mixture was concentrated,
the residue was subjected to phase separation with ethyl acetate (18 mL) and 1 N hydrochloric
acid (2. 5 mL), and the aqueous layer was extracted with ethyl acetate (18 mL). The
organic layer was washed with saturated brine (5 mL, twice), dried over sodium sulfate,
and then concentrated to give a yellow oily substance (0.182 g). The obtained yellow
oily substance was dissolved in isopropyl alcohol (0.08 mL) -ethyl acetate (0.8 mL).
To this, an ethyl acetate solution (0.4 mL) of dicyclohexylamine (0.094 g, 1 eq.)
was added, and then ethyl acetate (2.0 mL) was further added. The mixture was stirred
at room temperature for 9 hours. The precipitated crystals were separated by filtration,
and then blow-dried at 50°C to give a Z-L-phenylalanine DCHA salt (0.178 g, yield:
76%, 99.0% ee) as white crystals.
[0145] The product of this Example was analyzed under HPLC conditions-2': Z-Phe chiral analysis
conditions 2. The results are shown in Fig. 8.
Example 3-2: Release of D-phenylalanine from nickel (II) complex having D-phenylalanine
moiety (obtained by deracemization of racemic mixture of phenylalanine or by chiral
inversion of L-phenylalanine) in acid condition, and protection with Z-group
[0146]
[0147] To a methanol suspension (12 mL) of a nickel (II) complex having a D-phenylalanine
moiety (0.4 g, 0.53 mmol), 1 N hydrochloric acid (3.2 mL, 6 eq.) was added, and the
mixture was stirred at 40°C for 6 hours. After the end of the reaction, the reaction
mixture was concentrated, and the residue was dissolved in ethyl acetate (20 mL).
The organic layer was sequentially extracted with water (4 mL), 1 N hydrochloric acid
(4 mL), and water (4 mL). The obtained organic layer was sequentially washed with
a saturated sodium hydrogencarbonate aqueous solution (4 mL), water (4 mL), and saturated
brine (4 mL), and then dried over sodium sulfate. The sodium sulfate was filtered
off, and the filtrate was concentrated to dryness to give a chiral auxiliary (0.29
g, yield: 96%) as a pale yellow solid.
[0148] Meanwhile, the aqueous layer resulting from the extraction (12 mL) was concentrated
to dryness. The obtained solid was dissolved in 13% aqueous ammonia (4 mL) and passed
through a cation exchange resin column (made by Mitsubishi Chemical Corp. , trade
name: SK1B, 30 mL, eluent: water and subsequently aqueous ammonia (8%)) to give phenylalanine
(0.102 g, crude product, quantitative).
[0149] To the phenylalanine (0.102 g), an aqueous solution (3 mL) of sodium hydrogencarbonate
(0.090 mg, 2 eq.)-sodium carbonate (0.057 mg, 1 eq.), and acetone (1 mL) were added
to dissolve the phenylalanine. To the solution in an ice bath, an acetone solution
(2 mL) of N-benzyloxycarbonyloxy succinimide (0.139 g, 1.04 eq.) was added, and the
mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated,
and the residue was subjected to phase separation with water (17 mL) and toluene (1
mL). To the aqueous layer, a 10% aqueous solution of citric acid was added to adjust
the pH to 3, and then extraction with ethyl acetate (30 mL, 15 mL) was performed.
The organic layers were washed with water (2 mL) and saturated brine (2 mL, 3 times),
dried over sodium sulfate, and then concentrated to give a yellow oily substance (0.161
g, crude product, quantitative).
[0150] The obtained yellow oily substance was dissolved in isopropyl alcohol (0.01 mL)-ethyl
acetate (0.6 mL). To this, an ethyl acetate solution (0.1 mL) of dicyclohexylamine
(0.097 g, 1 eq.) was added, and then ethyl acetate (0.9 mL) and hexane (3 mL) were
further added. The mixture was stirred at room temperature overnight. The precipitated
crystals were separated by filtration, and then vacuum-dried at 50°C to give a Z-D-phenylalanine
DCHA salt (0.247 g, yield: 96%, 99.0% ee, abbreviated as Z-Phe) as white crystals.
[0151] The product of this Example was analyzed under HPLC conditions-2: Z-Phe chiral analysis
conditions 1. The results are shown in Fig. 9.
Example 3-3: Release of D-lysine from nickel (II) complex having D-lysine moiety (obtained
by chiral inversion of L-lysine) in acid condition, and protection with Z-group
[0152]
[0153] To a methanol suspension (6 mL) of a nickel (II) complex having a D-lysine moiety
(0.2 g, 0.27 mmol), 1 N hydrochloric acid (1.6 mL, 6 eq.) was added, and the mixture
was stirred at 40°C for 4 hours. After the end of the reaction, the reaction mixture
was concentrated, and the residue was dissolved in ethyl acetate (10 mL). The organic
layer was sequentially extracted with water (10 mL, 5 mL, 5 mL). The obtained organic
layer was sequentially washed with a saturated sodium hydrogencarbonate aqueous solution
(5 mL), water (5 mL), and saturated brine (5 mL), and then dried over sodium sulfate.
The sodium sulfate was filtered off, and the filtrate was concentrated to dryness
to give a chiral auxiliary (0.14 g, yield: 93%) as a pale yellow solid.
[0154] Meanwhile, the aqueous extraction liquid (20 mL) was washed with a small amount of
methylene chloride, and then concentrated to dryness. The obtained solid was dissolved
in water-methanol and a small amount of aqueous ammonia (1 mL) and passed through
a cation exchange resin column (made by Mitsubishi Chemical Corp., trade name: SK1B,
3 mL, eluent: water and subsequently aqueous ammonia (8%)) to give D-lysine (0.038
g, crude product) .
[0155] To the D-lysine (0.034 g), an aqueous solution (1 mL) of sodium hydrogencarbonate
(0.079 mg, 4 eq.)-sodium carbonate (0.050 mg, 2 eq.), and THF (1 mL) were added to
dissolve the lysine. To the solution in an ice bath, a THF solution (2.5 mL) of N-benzyloxycarbonyloxy
succinimide (0.118 g, 2 eq.) was added, and the mixture was stirred at room temperature
for 2 hours. The reaction mixture was concentrated, and the obtained residue was subjected
to phase separation with water (10 mL) and toluene (1 mL). To the aqueous layer, a
10% aqueous solution of citric acid was added to adjust the pH to 3, and then extraction
with ethyl acetate (15 mL, 10 mL, 5 mL) was performed. The organic layers were washed
with water (2 mL, twice) and saturated brine (5 mL, twice), and then dried over sodium
sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated. The
obtained yellow oily substance (0.102 g, crude product, yield: 93%) was purified by
silica gel column chromatography to give D-lysine protected by a Z group (Z-D-Lys(Z))
(0.082 g) as an oily substance. The obtained colorless oily substance (0.064 g) was
dissolved in isopropyl alcohol (0.01 mL)-ethyl acetate (0.6 mL). To this, an ethyl
acetate solution (0. 1 mL) of dicyclohexylamine (0. 028 g, 1 eq.), ethyl acetate (0.9
mL), and hexane (3 mL) were added, and the mixture was stirred at room temperature
overnight. The precipitated crystals were separated by filtration, and then vacuum-dried
at 50°C to give a Z-D-Lys(Z) DCHA salt (0.084 g, yield: 69% (yield from Ni (II) complex),
93.2% ee) as white crystals.
[0156] The product of this Example was analyzed under HPLC conditions-4: Z-D-Lys(Z) chiral
analysis conditions. The results are shown in Fig. 10.
Example 4. Deracemization
Example 4-1: Synthesis of D-phenylalanine by deracemization of DL-phenylalanine
[0157]
Example 4-1-1: Case where DL-phenylalanine (2 eq.), nickel acetate tetrahydrate (2
eq.), and potassium carbonate (6 eq.) are used relative to chiral auxiliary
[0158] To a methanol suspension (4 mL) of (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.2 g, 0.353 mmol), nickel acetate tetrahydrate
(0.176 g, 0.706 mmol), DL-phenylalanine (0.117 g, 0.706 mmol), and potassium carbonate
(0.293 g, 2.118 mmol) were added, and the mixture was refluxed for 24 hours. After
the end of the reaction, the reaction mixture was added to an ice-cooled 5% acetic
acid aqueous solution (15 mL) and stirred for 30 minutes to allow crystals to precipitate.
The crystals were separated by filtration, and then blow-dried at 50°C to give a nickel
(II) complex having a D-phenylalanine moiety (0.234 g, yield: 86%, 99% de) as red
crystals.
ESI-MS (positive mode): m/z = 770.2 for [M + H]
+.
1H-NMR (200 MHz, CDCl
3) : δ 2.42 [1H, d, J = 12.3 Hz, one of azepine C(α)H
2N], 2.59 (1H, H
A of ABX type, J
AB = 13. 6 Hz, J
AX = 5. 3 Hz, one of Phe β-CH
2), 2.61 [1H, d, J = 15.5 Hz, one of azepine C(α')H
2N], 2.76 and 3.18 (1H each, ABq, J = 13.9 Hz, acetanilide NCOCH
2), 3.00 (1H, H
B of ABX type, J
AB = 13.6 Hz, J
BX = 3.0 Hz, one of Pheβ-CH
2), 3.68 [1H, d, J = 15.5 Hz, one of azepine C(α')H
2N], 4.22 (1H, H
X of ABX type, J
AX = 5. 3 Hz, J
BX = 3.0 Hz, α-H of Phe part), 4.54 [1H, d, J = 12.3 Hz, one of azepine C (α)H
2N], 6.67 (1H, d, J = 2.4 Hz), 7.05-7.64 (15H, m, ArH), 7.66-7.85 (3H, m, ArH), 7.90-7.99
(3H, m, ArH), 8.09 (1H, d, J = 8.2 Hz, ArH), 8.35 (1H, d, J = 9.2 Hz, ArH), 8.67 (1H,
d, J = 8.2 Hz, ArH).
13C-NMR (50.3 MHz, CDCl
3) : δ 39.1 (β-CH
2 of Phe part), 57.6 (NCOCH
2), 61.6 and 65.9 (2 × CH
2 of azepine), 72.1 (α-CH of Phe part), 125.2 (ArCH), 126.1 (quaternary ArC), 126.3
(ArCH), 127.1 (ArCH), 127.5 (ArCH), 127.6 (ArCH), 127.7 (ArCH), 127.8 (ArCH), 128.4
(ArCH), 128.6 (ArCH), 128.8 (quaternary ArC), 128.95 (ArCH), 129.02 (ArCH), 129.3
(ArCH), 129.4 (ArCH), 130.4 (ArCH), 131.0 (quaternary ArC), 131.2 (quaternary ArC),
131.5 (quaternary ArC), 131.8 (ArCH), 132.4 (ArCH), 132.7 (ArCH), 133.0 (quaternary
ArC), 133.6 (quaternary ArC), 134.0 (quaternary ArC), 135.4 (quaternary ArC), 135.9
(quaternary ArC), 136.5 (quaternary ArC), 141.4 (quaternary ArC), 169.9, 174.3, 177.4
(CN and 2 × CO).
[0159] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 11.
[0160] D-phenylalanine can be obtained by processing this complex in the same manner as
in Example 3.
Example 4-1-2: Case where DL-phenylalanine (1.1 eq.), nickel acetate tetrahydrate
(1.1eq.), and potassium carbonate (4 eq.) are used relative to chiral auxiliary
[0161] To a methanol suspension (4 mL) of (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o [2,1-c:1',2'-e] azepin-4-yl] acetamide (0.2 g, 0.353 mmol), nickel acetate tetrahydrate
(0.97 g, 0.388 mmol), DL-phenylalanine (0.64 g, 0.388 mmol), and potassium carbonate
(0.195 g, 1.411 mmol) were added, and the mixture was refluxed for 24 hours. After
the end of the reaction, the reaction mixture was added to an ice-cooled 5% acetic
acid aqueous solution (15 mL) and stirred for 30 minutes to allow crystals to precipitate.
The crystals were separated by filtration, and then blow-dried at 50°C to give a nickel
(II) complex having a D-phenylalanine moiety (0.246 g, yield: 90.5%, 97.2% de) as
red crystals.
[0162] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 12.
[0163] D-phenylalanine can be obtained by processing this complex in the same manner as
in Example 3.
Example 4-2: Synthesis of L-phenylalanine by deracemization of DL-phenylalanine
[0164]
Example 4-2-1 : Case where DL-phenylalanine (2 eq.), nickel acetate tetrahydrate (2
eq.), and potassium carbonate (6 eq.) are used relative to chiral auxiliary
[0165] To a methanol suspension (16 mL) of (R)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.8 g, 1.411 mmol), nickel acetate tetrahydrate
(0.702 g, 2.821 mmol), DL-phenylalanine (0.466g, 2.821mmol), and potassium carbonate
(1.170 g, 8.464 mmol) were added, and the mixture was refluxed for 24 hours. After
the end of the reaction, the reaction mixture was added to an ice-cooled 5% acetic
acid aqueous solution (120 mL) and stirred for 30 minutes to allow crystals to precipitate.
The crystals were separated by filtration, and then blow-dried at 50°C to give a nickel
(II) complex having an L-phenylalanine moiety (1.035 g, yield: 95.2%, 99% de) as red
crystals.
ESI-MS (positive mode): m/z = 770.3 for [M + H]
+.
1H-NMR (200 MHz, CDCl
3): δ 2.42 [1H, d, J = 12.1 Hz, one of azepine C(α)H
2N], 2.59 (1H, H
A of ABX type, J
AB = 13. 6 Hz, J
AX = 5. 5 Hz, one of Pheβ-CH
2), 2.61 [1H, d, J = 15.6 Hz, one of azepine C(α')H
2N], 2.76 and 3.17 (1H each, ABq, J = 13.9 Hz, acetanilide NCOCH
2), 3.00 (1H, H
B of ABX type, J
AB = 13.6 Hz, J
BX = 3.0 Hz, one of Phe β-CH
2), 3.68 [1H, d, J = 15.6 Hz, one of azepine C(α')H
2N], 4.23 (1H, H
X of ABX type, J
AX = 5. 5 Hz, J
BX = 3.0 Hz, α-H of Phe part), 4.54 [1H, d, J = 12.1 Hz, one of azepine C(α)H
2N], 6.67 (1H, d, J = 2.4 Hz), 7.05-8.02 (21H, m, ArH), 8.09 (1H, d, J = 8.4 Hz, ArH),
8.34 (1H, d, J = 9.2 Hz, ArH), 8.68 (1H, d, J = 8.2 Hz, ArH).
13C-NMR (50.3 MHz, CDCl
3) : δ39.0 (β-CH
2 of Phe part), 57.5 (NCOCH
2), 61.6 and 65.9 (2 CH
2 of azepine), 72.1 (α-CH of Phe part), 125.2 (ArCH), 126.1 (quaternary ArC), 126.4
(ArCH), 127.1 (ArCH), 127.4 (ArCH), 127.5 (ArCH), 127.7 (ArCH), 127.8 (ArCH), 128.4
(ArCH), 128.6 (ArCH), 128.8 (quaternary ArC), 129.0 (ArCH), 129.1 (ArCH), 129.3 (ArCH),
129.4 (ArCH), 130.5 (ArCH), 131.0 (quaternary ArC), 131.2 (quaternary ArC), 131.4
(quaternary ArC), 131.8 (ArCH), 132.4 (ArCH), 132.7 (ArCH), 132.9 (quaternary ArC),
133.6 (quaternary ArC), 133.9 (quaternary ArC), 135.3 (quaternary ArC), 135.9 (quaternary
ArC), 136.5 (quaternary ArC), 141.4 (quaternary ArC), 169.9, 174.3, 177.4 (CN and
2 x CO).
[0166] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 13.
[0167] L-phenylalanine can be obtained by processing this complex in the same manner as
in Example 3.
Example 4-2-2 : Case where DL-phenylalanine (1.1 eq.), nickel acetate tetrahydrate
(1.1 eq.), and potassium carbonate (4 eq.) are used relative to chiral auxiliary
[0168] To a methanol suspension (4 mL) of (R)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.2 g, 0.353 mmol), nickel acetate tetrahydrate
(0.097 g, 0.388 mmol), DL-phenylalanine (0.064 g, 0.388 mmol), and potassium carbonate
(0.195 g, 1.411 mmol) were added, and the mixture was refluxed for 24 hours. After
the end of the reaction, the reaction mixture was added to an ice-cooled 5% acetic
acid aqueous solution (30 mL) and stirred for 30 minutes to allow crystals to precipitate.
The crystals were separated by filtration, and then blow-dried at 50°C to give a nickel
(II) complex having an L-phenylalanine moiety (0.250 g, yield: 92.1%, 97% de) as red
crystals.
[0169] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 14.
[0170] L-phenylalanine can be obtained by processing this complex in the same manner as
in Example 3-1.
Example 4-3: Synthesis of D-valine by deracemization of DL-valine
[0171]
[0172] To a methanol suspension (4 mL) of (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.2 g, 0.353 mmol), nickel acetate tetrahydrate
(0.176 g, 0.706 mmol), DL-valine (0.083 g, 0.706 mmol), and potassium carbonate (0.293
g, 2.118 mmol) were added, and the mixture was refluxed for 27 hours. After the end
of the reaction, the reaction mixture was added to an ice-cooled 5% acetic acid aqueous
solution (15 mL) and stirred for 30 minutes to allow crystals to precipitate. The
crystals were separated by filtration, and then blow-dried at 50°C to give a nickel
(II) complex having a D-valine moiety (0.203 g, yield: 79.6%, 92.4% de) as red crystals.
ESI-MS (positive mode): m/z = 722.2 for [M + H]
+.
1H-NMR (200 MHz, CDCl
3) : δ0.80 (3H, d, J = 7.0 Hz, Me), 1.79 (1H, doubtet of septets, J = 3.5, 7.0 Hz,
CHMe
2), 2.18 (3H, d, J = 6.8 Hz, Me), 2.54 [1H, d, J = 12.3 Hz, one of azepine C(α)H
2N], 3.02 [1H, d, J = 15.6 Hz, one of azepine C(α')H
2N], 3.64 and 3.75 (1H each, ABq, J = 13.9 Hz, acetanilide NCOCH
2), 3.72 (1H, d, J = 3.3 Hz, α-H of Val part), 4.54 [1H, d, J = 15.6 Hz, one of azepine
C(α')H
2N], 4.73 [1H, d, J = 12.3 Hz, one of azepine C(α)H
2N], 6.55 (1H, d, J = 2.4 Hz), 6.84-6.95 (2H, m, ArH), 7.14-7.55 (10H, m, ArH), 7.55
(1H, d, J = 8.4 Hz, ArH), 7.92-8.04 (3H, m, ArH), 8.19 (1H, d, J = 8.2 Hz, ArH), 8.44
(1H, d, J = 9.0 Hz, ArH), 8.99 (1H, d, J = 8.2 Hz, ArH).
13C-NMR (50.3 MHz, CDCl
3): δ18.5 and 19.7 (2 × Me of Val part), 34.5 (β-CH of Val part), 59.1 (NCOCH
2), 61.5 and 66.7 (2 × CH
2 of azepine), 75.9 (α-CH of Val part), 125.0 (ArCH), 126.1 (quaternary ArC), 126.37
(ArCH), 126.44 (ArCH), 127.1 (ArCH), 127.2 (ArCH), 127.4 (ArCH), 127.8 (ArCH), 128.0
(ArCH), 128.4 (ArCH), 128.55 (quaternary ArC), 128.62 (quaternary ArC), 128.7 (ArCH),
128.9 (ArCH), 129.1 (ArCH), 129.5 (ArCH), 130.1 (ArCH), 131.0 (quaternary ArC), 131.2
(quaternary ArC), 131.5 (quaternary ArC), 132.4 (ArCH), 132.5 (ArCH), 132.7 (quaternary
ArC), 133.7 (quaternary ArC), 134.1 (quaternary ArC), 135.4 (quaternary ArC), 136.0
(quaternary ArC), 141.0 (quaternary ArC), 169.7, 174.3, 176.3 (CN and 2 x CO).
[0173] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 15. D-valine can be obtained by processing
this complex in the same manner as in Example 3.
Example 4-4: Synthesis of L-valine by deracemization of DL-valine
[0174]
[0175] To a methanol suspension (4 mL) of (R)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.2 g, 0.353 mmol), nickel acetate tetrahydrate
(0.176 g, 0.706 mmol), DL-valine (0.083 g, 0.706 mmol), and potassium carbonate (0.293
g, 2.118 mmol) were added, and the mixture was refluxed for 24 hours. After the end
of the reaction, the reaction mixture was added to an ice-cooled 5% acetic acid aqueous
solution (30 mL) and stirred for 30 minutes to allow crystals to precipitate. The
crystals were separated by filtration, and then blow-dried at 50°C to give a nickel
(II) complex having an L-valine moiety (0.232 g, yield: 91.0%, 95% de) as red crystals.
[0176] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 16.
[0177] L-valine can be obtained by processing this complex in the same manner as in Example
3.
Example 4-5: Synthesis of D-alanine by deracemization of DL-alanine
[0178]
[0179] To a methanol suspension (4 mL) of (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.2 g, 0.353 mmol), nickel acetate tetrahydrate
(0.176 g, 0.706 mmol), DL-alanine (0.063 g, 0.706 mmol), and potassium carbonate (0.293
g, 2.118 mmol) were added, and the mixture was refluxed for 24 hours. After the end
of the reaction, the reaction mixture was added to an ice-cooled 5% acetic acid aqueous
solution (15 mL) and stirred for 30 minutes to allow crystals to precipitate. The
crystals were separated by filtration, and then blow-dried at 50°C to give a nickel
(II) complex having a D-alanine moiety (0.208 g, yield: 84.8%, 95.8% de) as red crystals.
[0180] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 17.
[0181] D-alanine can be obtained by processing this complex in the same manner as in Example
3.
Example 4-6: Synthesis of L-alanine by deracemization of DL-alanine
[0182]
[0183] To a methanol suspension (4 mL) of (R)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.2 g, 0.353 mmol), nickel acetate tetrahydrate
(0.176 g, 0.706 mmol), DL-alanine (0.063 g, 0.706 mmol), and potassium carbonate (0.293
g, 2.118 mmol) were added, and the mixture was heated at 40°C for 24 hours. After
the end of the reaction, the reaction mixture was added to an ice-cooled 5% acetic
acid aqueous solution (30 mL) and stirred for 30 minutes to allow crystals to precipitate.
The crystals were separated by filtration, and then blow-dried at 50°C to give a nickel
(II) complex having an L-alanine moiety (0.207 g, yield: 84.8%, 96% de) as red crystals.
ESI-MS (positive mode): m/z = 694.2 for [M + H]
+.
1H-NMR (200 MHz, CDCl
3) : δ1.51 (3H, d, J = 7.0 Hz, Me), 2.73 [1H, d, J = 12.2 Hz, one of azepine C(α)H
2N], 3.08 [1H, d, J = 15.6 Hz, one of azepine C(α')H
2N], 3.68 and 3.76 (1H each, ABq, J = 13.9 Hz, acetanilide NCOCH
2), 3.84 (1H, q, J = 7.0 Hz, α-H of Ala part), 4.57 [1H, d, J = 15.6 Hz, one of azepine
C(α')H
2N], 4.84 [1H, d, J = 12.1 Hz, one of azepine C(α)H
2N], 6.66 (1H, d, J = 2.6 Hz), 6.91-6.99 (1H, m, ArH), 7.16-7.32 (4H, m, ArH), 7.35-7.41
(1H, m, ArH), 7.43-7.57 (7H, m, ArH), 7.94-8.03 (3H, m, ArH), 8.16 (1H, d, J = 8.3
Hz, ArH), 8.44 (1H, d, J = 9.2 Hz, ArH), 8.76 (1H, d, J = 8.3 Hz, ArH).
13C-NMR (50.3 MHz, CDCl
3) : δ 21.5 (Me of Ala part), 58.7 (NCOCH
2), 61.9 and 66.3 (2 × CH
2 of azepine), 66.9 (α-CH of Ala part), 125.1 (ArCH), 126.1 (quaternary ArC), 126.37
(quaternary ArC), 126.44 (ArCH), 126.9 (ArCH), 127.3 (ArCH), 127.4 (ArCH), 127.5 (ArCH),
127.6 (ArCH), 127.8 (ArCH), 128.2 (quaternary ArC), 128.4 (ArCH), 128.7 (ArCH), 129.2
(ArCH), 129.5 (ArCH), 130.2 (ArCH), 131.0 (quaternary ArC), 131.3 (quaternary ArC),
131.5 (quaternary ArC), 132.4 (ArCH), 132.6 (ArCH), 132.7 (quaternary ArC), 133.7
(quaternary ArC), 134.1 (quaternary ArC), 135.6 (quaternary ArC), 136.0 (quaternary
ArC), 140.9 (quaternary ArC), 170.2, 174.6, 179.7 (CN and 2 × CO).
[0184] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 18.
[0185] L-alanine can be obtained by processing this complex in the same manner as in Example
3-1.
Example 4-7: Synthesis of D-tyrosine by deracemization of DL-tyrosine
[0186]
[0187] To a methanol suspension (1 mL) of (S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth
o[2,1-c:1',2'-e]azepin-4-yl]acetamide (0.2 g, 0.352 mmol), nickel chloride (0.0913
g, 0.704 mmol), DL-tyrosine (0.128 g, 0.704 mmol), and potassium carbonate (0.293
g, 2.18 mmol) were added, and the mixture was refluxed for 18 hours. After the end
of the reaction, the reaction mixture was added to an ice-cooled 5% acetic acid aqueous
solution (80 mL) and stirred for 30 minutes to allow crystals to precipitate. The
crystals were separated by filtration, and then vacuum-dried at 50°C to give a nickel
(II) complex having a D-tyrosine moiety (0.273 g, yield: 98.4%, 92.6% de) as an orange-red
solid.
ESI-MS (positive mode): m/z = 786.4 for [M + H]
+.
1H-NMR (200 MHz, CDCl
3) : δ 2.44 [1H, d, J = 12.1 Hz, one of azepine C(α) H
2N], 2.49 (1H, H
A of ABX type, J
AB = 13.9 Hz, J
AX = 4.9 Hz, one of Tyr β-CH
2), 2.71 [1H, d, J = 15.7 Hz, one of azepine C(α')H
2N], 2.92 (1H, H
B of ABX type, J
AB = 13.9 Hz, J
BX = 2.7 Hz, one of Tyr β-CH
2), 2.99 and 3.19 (1H each, ABq, J = 13.9 Hz, acetanilide NCOCH
2), 3. 92 [1H, d, J = 15.7 Hz, one of azepine C(α')H
2N], 4.18 (1H, H
X of ABX type, J
AX = 4.9 Hz, J
BX = 2.7 Hz, α-H of Tyr part), 4.59 [1H, d, J = 12.1 Hz, one of azepine C(α) H
2N], 6.67 (1H, d, J = 2.6 Hz), 6.93-7.00 (1H, m, ArH), 7.09-7.62 (16H, m, ArH), 7.77
(1H, d, J = 7.9 Hz, ArH), 7.81 (1H, d, J = 7.7 Hz, ArH), 7.92 (1H, d, J = 8.2 Hz,
ArH), 8.09 (1H, d, J = 8.2 Hz, ArH), 8.32 (1H, d, J = 9.0 Hz, ArH), 8.56 (1H, br,
OH), 8.70 (1H, d, J = 8.4 Hz, ArH).
13C-NMR (50.3 MHz, CDCl
3) : δ38.3 (β-CH
2 of Tyr part), 57.6 (NCOCH
2), 61.8 and 65.8 (2 × CH
2 of azepine), 72.4 (α-CH of Tyr part), 125.3 (ArCH), 126.3 (ArCH), 126.4 (ArCH), 126.5
(quaternary ArC), 126.9 (quaternary ArC), 127.1 (ArCH), 127.4 (ArCH), 127.5 (ArCH),
127.7 (ArCH), 128.4 (ArCH), 128.55 (ArCH), 128.59 (quaternary ArC), 128.8 (quaternary
ArC), 129.1 (ArCH), 129.4 (ArCH), 130.5 (ArCH), 130.9 (quaternary ArC), 131.1 (quaternary
ArC), 131.3 (quaternary ArC), 132.5 (ArCH), 132.6 (ArCH), 132.7 (quaternary ArC),
133.5 (quaternary ArC), 133.9 (quaternary ArC), 135.2 (quaternary ArC), 136.0 (quaternary
ArC), 140.7 (quaternary ArC), 157.0 (quaternary ArC), 169.9, 174.9, 177.9 (CN and
2 × CO).
[0188] The product of this Example was analyzed under HPLC conditions-1: complex analysis
conditions. The results are shown in Fig. 19.
Industrial Applicability
[0189] According to the present invention, by using an appropriately selected optical isomer
of a novel N-(2-acylaryl)-2-[5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl]ac etamide compound
as a chiral template, the chirality of an α-amino acid can be interconverted to give
an α-amino acid having a desired chirality in high yield and in a highly enantioselective
manner. In particular, the present invention is useful for the production of an optically
active unnatural α-amino acid.